bims-hemali Biomed News
on Hematologic malignancies
Issue of 2026–10–25
27 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Frontline Bruton tyrosine kinase inhibitors are associated with improved response and PFS in primary CNS lymphoma.
  2. Glofitamab with polatuzumab vedotin in relapsed/refractory central nervous system lymphomas.
  3. High Initial Dose and Accelerated vs. Slow Titration Ropeginterferon Alfa-2b for Polycythemia Vera: A Meta-Analysis.
  4. One CAR is good; are 2 CARs better?
  5. Efficacy and Safety of an Orelabrutinib-Based Oral Induction Regimen in Central Nervous System Lymphoma: A Real-World Study.
  6. Real-world outcomes of asciminib versus first- and second-generation tyrosine kinase inhibitors as second-line treatment for chronic-phase chronic myeloid leukemia.
  7. Pirtobrutinib for the Treatment of Therapy-Resistant Chronic Lymphatic Leukemia With CNS Localization.
  8. Molecular predictors of minimal residual disease in newly diagnosed multiple myeloma treated with quadruplet therapy.
  9. Current perspectives on high-risk genomic profiles in chronic myeloid leukemia: from bench to clinical practice.
  10. Degrading the BTK and blocking BCL2: a new path in marginal zone lymphomas.
  11. Firstline treatment with ruxolitinib versus best available therapy in patients with polycythemia vera: results from the randomized RuxoBEAT trial.
  12. Ferritin screening in pregnancy.
  13. Real-world outcomes of mosunetuzumab use in relapsed/refractory indolent lymphomas: a CUBIC consortium analysis.
  14. Reframing APS thrombogenesis: a new PF4-driven mechanism.
  15. Reshaping the definition of high-risk disease in the immune effector therapy era in multiple myeloma.
  16. A novel CD123xVδ2 bispecific T cell engager induces potent and tumor selective Vγ9Vδ2-T cell activity against CD123 expressing acute myeloid leukemia and myelodysplastic syndrome.
  17. Rusfertide for Polycythemia Vera: Incremental Benefit Assessment.
  18. Recognizing Fluid Overload-Associated Large B-Cell Lymphoma on Effusion Cytology: Two Illustrative Cases.
  19. Lead Optimization of an Aminopyrazole Scaffold to EXEL-1855, a Highly Selective PLK4 Inhibitor with Potent Antitumor Efficacy.
  20. Potential Role of BCL2 and BCL6 Overexpression in Circulating Tumor Cells as Molecular Biomarkers in DLBCL After R-CHOP Therapy.
  21. Maintenance ALK inhibitor after hematopoietic cell transplantation in patients with anaplastic large cell lymphoma.
  22. Characterization of the morphological, immunophenotypical and cytogenetic features of high-grade B-cell lymphoma with 11q aberration.
  23. Newly diagnosed and relapsed follicular lymphoma: EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up.
  24. CD8 T-cell exhaustion linked with CAR T-cell failure can be mitigated by a non-alpha IL2 receptor agonist.
  25. Case Report: Durable, well-tolerated complete response to epcoritamab plus pirtobrutinib in Richter transformation relapsing after CD19 CAR T-cell therapy.
  26. Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
  27. Long-term hydroxyurea therapy alters bone marrow megakaryocyte morphology and associates with prognosis in myeloproliferative neoplasms.
  1. Blood Adv. 2026 Oct 23. pii: bloodadvances.2026020093. [Epub ahead of print]
    Frontline Bruton tyrosine kinase inhibitors are associated with improved response and PFS in primary CNS lymphoma.
    Xiaoxiao Wang, Bing Bai, Shanshan Yu, Lei Wen, Xingyuan Shi, Huiqiang Huang.
      High-dose methotrexate (HD-MTX)-based immunochemotherapy remains the standard for primary CNS lymphoma (PCNSL), yet relapse rates are high and outcomes suboptimal. While Bruton's tyrosine kinase inhibitors (BTKi) demonstrate efficacy in trials, their comparative benefit against conventional regimens in heterogeneous real-world populations remains undefined. We conducted a retrospective study of 131 newly diagnosed patients stratified by frontline induction therapy (BTKi-based, n=85; conventional, n=46), utilizing multiple imputation (m=50) and inverse probability of treatment weighting (IPTW) to balance baseline covariates. In the primary pooled multiple-imputation IPTW analysis, BTKi-based therapy was associated with improved PFS (HR 0.57, 95% CI 0.32-1.00; P=0.048) and a higher complete response rate (OR 5.50, 95% CI 2.25-13.47; P<0.001). The objective response rate was also higher (OR 2.59, 95% CI 1.05-6.36; P=0.038). The overall survival difference was not statistically significant (HR 0.65, 95% CI 0.31-1.38; P=0.263), which may reflect multifactorial confounding inherent in this retrospective comparison. These findings suggest that integrating BTKi into frontline regimens is associated with a favorable PFS profile and improved response in newly diagnosed PCNSL, while definitive OS conclusions cannot be drawn.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020093
  2. Blood Adv. 2026 Oct 21. pii: bloodadvances.2026022200. [Epub ahead of print]
    Glofitamab with polatuzumab vedotin in relapsed/refractory central nervous system lymphomas.
    Paolo Lopedote, Avyakta Kallam, Alexey V Danilov, Tycel J Phillips, Geoffrey Shouse, Brian Sworder, Azra Borogovac, Yan Liu, Joo Y Y Song, Alex F Herrera, James K Godfrey.
      Patients with relapsed/refractory (r/r) central nervous system lymphoma (CNSL) have poor survival with currently available treatments. Early reports suggest antibody-based treatments such as bispecific antibodies and antibody-drug conjugates can penetrate the blood-brain barrier and induce clinical responses in r/r CNSL. In this study, we retrospectively evaluated the safety and activity of glofitamab plus polatuzumab vedotin in 9 r/r CNSL patients treated at our institution, including high-risk subtypes such as chemorefractory Burkitt lymphoma and TP53-mutant Mantle cell lymphoma. Here, we observed a 100% overall and 89% complete response rate. Responses occurred in patients with brain parenchymal and leptomeningeal involvement, with rapid clearance of lymphoma cells from the cerebrospinal fluid within days of treatment as assessed by flow cytometry. Safety aligned with the known toxicity profile of the regimen in patients with systemic lymphomas. These data indicate glofitamab with polatuzumab vedotin is capable of safely inducing deep and rapid clinical remissions in r/r CNSL, including in high-risk histological and molecular subtypes. Future prospective evaluation of the regimen for r/r CNSL is warranted given the unmet need of this population.
    DOI:  https://doi.org/10.1182/bloodadvances.2026022200
  3. Blood Adv. 2026 Oct 21. pii: bloodadvances.2026020729. [Epub ahead of print]
    High Initial Dose and Accelerated vs. Slow Titration Ropeginterferon Alfa-2b for Polycythemia Vera: A Meta-Analysis.
    Abdulraheem Yacoub, Chun-Ting Wu, Shinya Imada, Albert Qin, Anthony Michael Hunter.
      Ropeginterferon alfa-2b (ropegIFN) is an approved cytoreductive therapy for polycythemia vera (PV). While the current drug label supports a low initial dose with slow titration ("Slow Titration") regimen starting at 50-100 μg with gradual escalation, there is increasing adoption of a high initial dose and accelerated titration (HIDAT) regimen, starting at 250 μg with rapid escalation to 500 μg in 4 weeks. We conducted a systematic review and meta-analysis of ropegIFN studies to derive pooled estimates of efficacy and safety outcomes across HIDAT and Slow Titration studies. We searched MEDLINE, Embase, Web of Science, and ClinicalTrials.gov for literature published up until 3/15/2026. Study selection, data extraction, and risk of bias assessment (ROB2, MINORS, Newcastle-Ottawa Scale) was performed with otto-SR, an AI-powered systematic review platform, with independent human validation. HIDAT achieved significantly higher complete hematologic response (CHR) rates at 3, 6, and 12 months, relative to Slow Titration. Molecular response rates and reductions of JAK2V617F VAF were similarly superior with HIDAT at 6 and 12 months. No significant differences in safety outcomes (adverse events, serious adverse events, trial discontinuations) were observed. These findings support the clinical rationale for HIDAT as a strategy to accelerate hematologic and molecular disease control in PV, while prospective randomized trials are needed to confirm the results.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020729
  4. Blood. 2026 Oct 22. 148(17): 2089-2090
    One CAR is good; are 2 CARs better?
    Salomon Manier.
      
    DOI:  https://doi.org/10.1182/blood.2026035159
  5. Blood Lymphat Cancer. 2026 ;16 619996
    Efficacy and Safety of an Orelabrutinib-Based Oral Induction Regimen in Central Nervous System Lymphoma: A Real-World Study.
    Yawen Wang, Wei Song, Shuxin Xiao, Haiyang Yu, Jigang Wang, Hongwei Xue.
       Purpose: To evaluate the efficacy and safety of an orelabrutinib-based RBTL regimen (rituximab, orelabrutinib, temozolomide, and pomalidomide) as an induction strategy for patients with central nervous system lymphoma (CNSL).
    Patients and methods: We retrospectively analyzed 40 patients with CNSL treated at the Affiliated Hospital of Qingdao University between April 2022 and January 2025, including 28 newly diagnosed and 12 relapsed/refractory patients. RBTL was administered as induction therapy, followed by individualized subsequent treatment, including high-dose methotrexate (HD-MTX)-based therapy, radiotherapy, autologous stem cell transplantation, or maintenance therapy. The primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, and safety.
    Results: Forty patients were evaluable for safety and 38 for efficacy. All 38 efficacy-evaluable patients received subsequent individualized therapy after RBTL induction, including HD-MTX-based therapy, radiotherapy, ASCT, or orelabrutinib maintenance. After RBTL induction, the ORR was 86.8% (33/38), including a complete response/unconfirmed complete response (CR/CRu) rate of 36.8%. After subsequent therapy, the best ORR was 94.7% (36/38), with a CR/CRu rate of 63.2%. With a median follow-up of 18.5 months, the 12-month PFS and OS rates were 74.7% (95% CI, 61.6-90.6%) and 71.3% (95% CI, 57.7-88.2%), respectively. Treatment-emergent adverse events occurred in 92.5% of patients, and 7.5% discontinued treatment because of adverse events. One treatment-related death occurred in association with severe thrombocytopenia.
    Conclusion: RBTL showed encouraging activity and manageable toxicity as an induction strategy for CNSL. Because most evaluable patients received subsequent individualized therapy, durable disease control should be interpreted in the context of the overall sequential treatment strategy. Larger prospective studies are warranted.
    Keywords:  CNS lymphoma; efficacy; orelabrutinib; pomalidomide; tolerance
    DOI:  https://doi.org/10.2147/BLCTT.S619996
  6. Leuk Res. 2026 Oct 13. pii: S0145-2126(26)00189-X. [Epub ahead of print]171 108345
    Real-world outcomes of asciminib versus first- and second-generation tyrosine kinase inhibitors as second-line treatment for chronic-phase chronic myeloid leukemia.
    Ehab L Atallah, Islam Sadek, Emily McGovern, Dominick Latremouille-Viau, Carmine Rossi, Remi Bellefleur, Nathan Gobeil, Gabriel Marquez, Annie Guérin, Daisy Yang, David Wei.
       BACKGROUND: This study compared real-world outcomes of patients with chronic myeloid leukemia in chronic phase (CML-CP) treated with asciminib and first/second generation (1 G/2 G) tyrosine kinase inhibitors (TKI) as second-line treatment (2 L) in the US.
    METHODS: A retrospective panel-based chart review from oncologists/hematologists was conducted on adult patients with CML-CP in 2 L treated with asciminib or 1 G/2 G TKIs between January 2022-June 2023 (index period). Entropy balancing was used to adjust baseline characteristics between asciminib and 1 G/2 G TKI cohorts. Time to discontinuation, progression to accelerated phase/blast crisis (AP/BC), BCR::ABL1 ≤ 0.1% (MMR), and BCR::ABL1 ≤ 0.01% (MR4) post-index were assessed using weighted Kaplan-Meier analyses and Gehan-Breslow tests.
    RESULTS: De-identified data on 255 patients (median age: 62.0, female: 43.5%, White: 56.1%) in the asciminib cohort were collected from 76 physicians (community/academic: 47.4/52.6%) and 233 patients (median age: 62.0, female: 43.3%, White: 56.2%) in the 1 G/2 G TKI cohort from 72 physicians (community/academic: 41.7/58.3%). By 48 weeks post-index, fewer patients in the asciminib (4.6%) versus 1 G/2 G TKI (10.4%) cohort experienced discontinuations (p = 0.07), and no patients progressed to AP/BC in the asciminib versus 4.2% in the 1 G/2 G TKI cohort (p < 0.05). By 48 weeks post-index, 68.3% of the asciminib versus 59.8% of the TKI cohort achieved or maintained MMR, and 40.6% versus 22.0% for MR4. Median time to MMR (MR4) was 30.7 (59.7) and 39.7 (72.7) weeks for the asciminib and 1 G/2 G TKI cohorts, respectively (all p < 0.05).
    CONCLUSIONS: Findings from this large real-world US study suggest that 2 L asciminib offers favorable tolerability and better effectiveness compared with 1 G/2 G TKIs for patients with CML-CP.
    Keywords:  Asciminib; Chronic myeloid leukemia in chronic phase; Effectiveness; Molecular response; Tolerability; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.leukres.2026.108345
  7. Case Rep Hematol. 2026 ;2026 1249723
    Pirtobrutinib for the Treatment of Therapy-Resistant Chronic Lymphatic Leukemia With CNS Localization.
    M E Roerink, A P Kater, S H Tonino, E van der Spek.
      During the last decade, many new treatment options for chronic lymphatic leukemia (CLL) have become available, one of them being covalent-binding Bruton's tyrosine kinase inhibitors (cBTK inhibitors [cBTKis]). There are currently three cBTKis approved for treatment of CLL/SLL: acalabrutinib, ibrutinib, and zanubrutinib. In relapsed and heavily pretreated patients, BTK inhibitors achieve a median PFS of 4 years, and in frontline, around 80% of CLL patients are still in remission and alive after 4 years of treatment with BTK inhibitors. Despite their efficacy, 40% of patients have to discontinue BTK inhibitors because of side effects or treatment resistance. We present the efficacy of the novel noncovalent BTKi in a patient with CLL who developed covalent BTKi-resistant disease with CNS localization. Pirtobrutinib appears to be effective in patients with ibrutinib resistance, even with CNS localization. Clinical responses may take several months to become evident.
    DOI:  https://doi.org/10.1155/crh/1249723
  8. Nat Med. 2026 Oct 19.
    Molecular predictors of minimal residual disease in newly diagnosed multiple myeloma treated with quadruplet therapy.
    Intergroupe Francophone du Myélome (IFM)
      Quadruplet therapy, combining anti-CD38 antibodies, immunomodulatory drugs, proteasome inhibitors and dexamethasone, is now the standard induction treatment for newly diagnosed multiple myeloma (NDMM). However, treatment response is heterogeneous and molecular predictors are needed to guide early therapeutic decisions. We performed integrated genomic, transcriptomic and epigenomic profiling of 423 tumor samples from patients with NDMM from the MIDAS cohort to characterize molecular heterogeneity and its association with measurable residual disease (MRD) after quadruplet induction with isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd). Postinduction MRD-negativity rates varied significantly across gene expression subtypes, with HP1/HP3 and MS groups showing superior responses compared to the MF and CD2 subtypes. B cell differentiation was associated with MRD positivity, while proliferation and MYC programs were associated with MRD negativity. These MRD-associated transcriptomic features were independently validated in the CASSIOPEIA cohort. Whole-genome sequencing revealed both known (APOBEC mutagenesis, chromothripsis) and new genomic instability phenotypes validated in the MMRF cohort. New driver alterations were identified with independent validation across three external cohorts with multiple myeloma (MMRF, MANHATTAN and CASSIOPEIA; 1,451 cases). Genomic instability features and driver genes such as CCND1 and MYC correlated with differential MRD outcomes. DNA methylation profiling identified nine MRD-linked subgroups distinguished by the extent of hypomethylation in quiescent chromatin and cis/trans signatures of driver translocations. A multimodal random forest model integrating genomic, transcriptomic and epigenomic features predicted MRD status after induction, with an area under the curve of 0.77, outperforming clinical and genomic models, while providing comparable discrimination and improved calibration relative to the transcriptomic and epigenomic models. These findings define a multiomic classification of NDMM linked to Isa-KRd response. ClinicalTrials.gov identifier: NCT04934475 .
    DOI:  https://doi.org/10.1038/s41591-026-04692-0
  9. Int J Hematol. 2026 Oct 21.
    Current perspectives on high-risk genomic profiles in chronic myeloid leukemia: from bench to clinical practice.
    Mohamed Isam Sharif, Agustina Maria Perusini, Hassan Sibai, Dennis Dong Hwan Kim.
      Chronic myeloid leukemia (CML) is defined by BCR::ABL1 rearrangement, yet its genomic architecture extends well beyond this single driver. High-risk genomic profiles (HGP)-additional chromosomal abnormalities in Philadelphia-positive cells, Philadelphia chromosome-associated rearrangements, and high-risk somatic mutations detected by next-generation sequencing (NGS)-are present at diagnosis in roughly one-third of chronic-phase (CP) patients and shape response, progression, and survival. We propose a clinically actionable taxonomy of HGP based on biological origin, detection method, and TKI sensitivity. Central to it is ASXL1, the most consequential somatic variant in CML. ASXL1 mutations are present in 7-14% of newly diagnosed CP patients and independently predict inferior response, treatment failure, and ABL1 kinase domain mutations, even with potent frontline tyrosine kinase inhibitors (TKIs), including asciminib. By contrast, the adverse impact of Ph-associated rearrangements is overcome by potent TKIs. A newly described sixth pattern of mutation dynamics-de novo DTA (DNMT3A, TET2, ASXL1) mutations in 24% of optimal responders with a median doubling time of 68 days-supports serial NGS monitoring every 6-7 months as a noninvasive complement to cytogenetics. We present a practical decision framework across the key management nodes of CML: diagnosis, monitoring, treatment failure, and blast phase.
    Keywords:   ASXL1 ; BCR::ABL1 kinase domain mutation; Additional genetic abnormalities; Blastic phase; Chronic myeloid leukemia; Clonal hematopoiesis; Next-generation sequencing; Precision medicine
    DOI:  https://doi.org/10.1007/s12185-026-04301-3
  10. Haematologica. 2026 Oct 22.
    Degrading the BTK and blocking BCL2: a new path in marginal zone lymphomas.
    Sylvain Carras.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.301998
  11. Blood Cancer J. 2026 Oct 22. pii: 189. [Epub ahead of print]16(1):
    Firstline treatment with ruxolitinib versus best available therapy in patients with polycythemia vera: results from the randomized RuxoBEAT trial.
    German Study Group for Myeloproliferative Neoplasms (GSG-MPN)
      Ruxolitinib (RUX) is approved as second-line treatment for HU-intolerant/-resistant patients with polycythemia vera (PV). Here, we assessed RUX vs. best available therapy (BAT) as first-line treatment in PV in the randomized multicenter RuxoBEAT clinical trial (NCT02577926). Crossover from BAT to RUX was possible after 6 months. Baseline characteristics in the RUX (n = 44) and BAT (n = 34) arms were comparable. The primary endpoint, the clinico-hematologic complete response (CR) rate at month 6, was not met (2.3% vs. 2.9%, p = 1.000). Analyses of secondary and exploratory endpoints showed that RUX was significantly more effective than BAT in improving hematocrit, splenomegaly, and patient-reported pruritus and fatigue, but less effective in reducing platelet counts. Compared to baseline, JAK2V617F variant allele frequency decreased significantly in both RUX and BAT groups at 6 months. The time on treatment (p < 0.001) and duration of treatment (p = 0.022) were significantly superior for RUX vs. BAT during the 24-month study period. There were no new safety signals. These findings demonstrate that RUX did not lead to higher CR rates than BAT and suggest that RUX may induce clinically meaningful additional disease improvements in first-line therapy of PV patients.
    DOI:  https://doi.org/10.1038/s41408-026-01644-2
  12. Blood Adv. 2026 Oct 21. pii: bloodadvances.2026022263. [Epub ahead of print]
    Ferritin screening in pregnancy.
    Mark Chaitowitz.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2026022263
  13. Blood Neoplasia. 2026 Nov;3(4): 100280
    Real-world outcomes of mosunetuzumab use in relapsed/refractory indolent lymphomas: a CUBIC consortium analysis.
    Andrew P Jallouk, Lorenzo Falchi, Ayushi Chauhan, Geoffrey Shouse, Swetha K Thiruvengadam, Yazeed Sawalha, Sonia Godbole, Ajay Major, Reid W Merryman, Shakthi T Bhaskar, Allison M Bock, Mehdi Hamadani, Amy Ayers, Omnia Farahat, Narendranath Epperla, Jennifer L Crombie, Steven Bair, Mathew A Lunning, Alex F Herrera, Christopher R Flowers, Gilles Salles, Sairah Ahmed.
      Mosunetuzumab (mosun) is a CD20 × CD3 bispecific antibody approved for follicular lymphoma. Despite promising results in clinical trials, there are limited real-world data to assess outcomes with mosun, particularly in patients with poor performance status or significant comorbidities. To address this need, we performed a multicenter retrospective study at 9 centers in the Collaborative US Bispecifics Consortium and identified 119 patients who received mosun for non-Hodgkin lymphoma. Ninety patients (75.6%) had indolent lymphomas, 26% of whom would not have been eligible for the mosun registrational trial. Of these patients, 97% received single-agent mosun. Overall response rate was 87%, and the complete response rate was 71%. With a median follow-up of 17.0 months, median progression-free survival (PFS) and overall survival (OS) were not reached. Eighteen-month PFS and OS estimates were 56.7% and 92.9%, respectively. Most cases of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome were low grade, with no differences in survival between trial-eligible and trial-ineligible patients. There was a higher rate of infections in trial-ineligible patients than in trial-eligible patients (45% vs 21%; P = .043). These findings support the use of mosun in the treatment of relapsed/refractory indolent lymphomas, even in trial-ineligible patients.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100280
  14. Blood. 2026 Oct 22. 148(17): 2096-2097
    Reframing APS thrombogenesis: a new PF4-driven mechanism.
    Beng H Chong.
      
    DOI:  https://doi.org/10.1182/blood.2026035161
  15. Front Oncol. 2026 ;16 1956522
    Reshaping the definition of high-risk disease in the immune effector therapy era in multiple myeloma.
    Yoshito Nishimura, Gunjan Gaur, Francesca Cottini, Saurabh Zanwar.
      Multiple myeloma (MM) outcomes have improved with proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and transplantation, yet a subset of patients with high-risk MM (HRMM) continues to relapse early and die prematurely. Immune effector therapies (IET)-B-cell maturation antigen (BCMA)- and G protein-coupled receptor class C group 5 member D (GPRC5D)-directed chimeric antigen receptor T cells (CAR-T) and bispecific antibodies-have transformed the treatment of relapsed/refractory MM. However, their benefit in HRMM remains incompletely defined. This review describes how HRMM is defined in the IET-era distinguishing baseline biological/genomic risk, clinical high-risk phenotypes, and IET-specific adverse predictors. The International Myeloma Society/International Myeloma Working Group consensus integrates adverse cytogenetics and beta-2 microglobulin, whereas functional high-risk disease, extramedullary disease (EMD), plasma cell leukemia (PCL), high tumor burden, inflammation, and prior BCMA exposure identify aggressive disease in relapsed patients. Across pivotal trials, CAR-T therapy, particularly ciltacabtagene autoleucel, and selected bispecific antibodies retain activity in high-risk cytogenetic subgroups, whereas EMD and PCL remain associated with inferior responses and short progression-free survival. Emerging dual-antigen and trispecific engagers, along with novel targets such as FcRH5 and CD70, aim to overcome antigen escape. Prospective, biology-informed studies are needed to achieve durable disease control in HRMM.
    Keywords:  CAR-T; bispecific antibody; high-risk myeloma; multiple myeloma; plasma cell leukemia
    DOI:  https://doi.org/10.3389/fonc.2026.1956522
  16. Clin Immunol. 2026 Oct 23. pii: S1521-6616(26)00124-5. [Epub ahead of print] 110786
    A novel CD123xVδ2 bispecific T cell engager induces potent and tumor selective Vγ9Vδ2-T cell activity against CD123 expressing acute myeloid leukemia and myelodysplastic syndrome.
    Jurjen M Ruben, Charlotte M Mousset, Dorien van de Berg, Kim Hofman, Milon de Jong, Patricia Brouwer, Sanne Graeve, Victoria Iglesias-Guimarais, Pauline M van Helden, Anton E P Adang, Rob C Roovers, Hans J van der Vliet.
      Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) have poor outcomes. We developed a humanized, half-life-extended CD123 × Vδ2 bispecific T-cell engager (bsTCE) to redirect Vγ9Vδ2 T cells to CD123-expressing malignancies. The engager bound selectively to Vγ9Vδ2 T cells and CD123-positive AML cells, with no detectable off-target interactions in specificity and tissue cross-reactivity assays. In vitro, it induced potent lysis of tumor cell lines and patient-derived AML and MDS cells, including at low effector-to-target cell ratios, supportive of serial killing. Compared with a CD123 × CD3 bsTCE, it induced lower levels of cytokines associated with cytokine release syndrome. Vγ9Vδ2-T cells preferentially lysed tumor cells over CD123-positive non-malignant cells, including plasmacytoid dendritic cells, and were detectable in patients' peripheral blood and bone marrow. The engager reduced tumor growth in an AML xenograft model and showed antibody-like pharmacokinetics in nonhuman primates. A phase 1 clinical trial was initiated (ACTRN12624001214527).
    Keywords:  Acute myeloid leukemia (AML); Bispecific T cell engager; CD123; Cancer immunotherapy; Myelodysplastic syndrome (MDS); Tumor-selective cytotoxicity; Vγ9Vδ2 T cells; γδ T cells
    DOI:  https://doi.org/10.1016/j.clim.2026.110786
  17. Am J Hematol. 2026 Oct 17.
    Rusfertide for Polycythemia Vera: Incremental Benefit Assessment.
    Ayalew Tefferi, Naseema Gangat, Paola Guglielmelli, Alessandro M Vannucchi, Tiziano Barbui.
      Rusfertide mechanism of action and clinical trial results in polycythemia vera.
    DOI:  https://doi.org/10.1002/ajh.70528
  18. Diagn Cytopathol. 2026 Oct 18.
    Recognizing Fluid Overload-Associated Large B-Cell Lymphoma on Effusion Cytology: Two Illustrative Cases.
    Selamawit Ayele, Tesfalem Korga, Sultan Pehlivan, Shweta Gera, Mark Suhrland, Jui Choudhuri.
      Fluid overload-associated large B-cell lymphoma (FO-LBCL) is a distinct entity introduced in the 5th edition of the WHO Classification of Hematolymphoid Tumors (2022). It denotes a large B-cell lymphoma confined to one or more serous cavities as effusions, without a solid or nodal mass, in the absence of KSHV/HHV8 (and largely EBV) infection, arising in patients with fluid-overload states. It was previously reported under descriptive terms such as "HHV8-negative primary effusion lymphoma-like lymphoma." We describe two cases illustrating the WHO-HAEM5 diagnostic criteria and the diagnostic and prognostic workup of this entity.
    Keywords:  HHV8‐negative; WHO‐HAEM5; cytopathology; effusion‐based lymphoma; fluid overload‐associated large B‐cell lymphoma; serous effusion
    DOI:  https://doi.org/10.1002/dc.70220
  19. J Med Chem. 2026 Oct 08. 69(19): 22637-22656
    Lead Optimization of an Aminopyrazole Scaffold to EXEL-1855, a Highly Selective PLK4 Inhibitor with Potent Antitumor Efficacy.
    Ryan L Gonciarz, Trevor Chang, Andre H St Amant, Joon Won Jeong, Danny Ng, Nigam M Mishra, Sanjay Bhattarai, Justin M Salvant, Jo-Ting Chang, Faming Jiang, Halesha Basavarajappa, Ziqiang Wang, David Cole, Huy H Nguyen, Jae H Chang, Aditya Kumar, Leo Mok, Wei Xu, John M Sanders, Deepak Gurbani, Dana M Gwinn, Brian A Sherer, Nina M Muñoz, Christopher Kochansky, Jeremy M Murray, Heather J Finlay.
      Polo-like kinase 4 (PLK4) is a serine/threonine kinase that has an essential role in regulating centriole duplication and centrosome biogenesis during cell-cycle progression and a potential therapeutic target in various human cancers. Structure-guided lead optimization of an aminopyrazole scaffold at three key vectors led to the identification of EXEL-1855, which demonstrated a significant improvement in cellular potency, increased selectivity over related-kinases and an improved pharmacokinetic profile. Targeting the non-conserved Met91 residue in the PLK4 lower hinge region and optimizing this interaction, enabled EXEL-1855 to be most selective PLK4 inhibitor reported to date. In a preclinical CHP-134 neuroblastoma mouse xenograft model, EXEL-1855 showed robust efficacy and was well-tolerated at all dose levels. Taken together, our medicinal chemistry campaign resulted in a highly optimized, orally bioavailable, and efficacious inhibitor of PLK4, with the potential to advance as an oral single-agent for the treatment of neuroblastoma with a projected human dose of 540 mg QD.
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c01844
  20. Rev Med Chil. 2026 Aug;pii: S0034-98872026000801210. [Epub ahead of print]154(8): 1210-1218
    Potential Role of BCL2 and BCL6 Overexpression in Circulating Tumor Cells as Molecular Biomarkers in DLBCL After R-CHOP Therapy.
    Rafael CerónMaldo Nado, Amairani Gutiérrez Nava, Adolfo Martínez Tovar, Christian Omar Ramos Peñafiel, Adrián De la Cruz Rosas, Anel Irais García Laguna, Iveth Mendoza Salas, Gilberto Israel Barranco Lampón, Carlos Martínez Murillo, Efreen Horacio Montaño Figueroa, Silvia Jiménez Morales, Irma Olarte Carrillo.
      Diffuse large B-cell lymphoma (DLBCL) is the most prevalent non-Hodgkin lymphoma subtype. Although R-CHOP remains the standard first-line therapy, up to 30% of patients experience relapse or refractory disease. Currently, therapeutic monitoring relies on imaging, which is less sensitive than molecular techniques for detecting residual disease.
    AIM: To evaluate BCL2 and BCL6 oncogene expression in Circulating Tumor Cells (CTCs) as potential molecular biomarkers for clinical outcomes in DLBCL patients after R-CHOP therapy.
    METHODS: We analyzed BCL2 and BCL6 expression in CTCs from 42 patients post-R-CHOP using immunomagnetic enrichment of CD20+ cells followed by RT-qPCR.
    RESULTS: Patients exhibited significantly higher BCL2 (p = 0.003) and BCL6 (p = 0.001) expression than healthy controls. Overexpression of BCL2 and BCL6 was observed in 16.7% and 19% of patients, respectively, with 9.5% showing co-expression. Normal BCL6 expression correlated with complete response (p = 0.004), and BCL6 demonstrated high discriminative ability for disease activity (AUC = 0.791, p = 0.008).
    CONCLUSIONS: The presence of BCL2 and BCL6 in CTCs suggests that liquid biopsy serves as a robust, complementary tool to PET/CT for post-treatment monitoring. These findings support the utility of BCL6 as a biomarker for residual disease surveillance in DLBCL.
    DOI:  https://doi.org/10.4067/s0034-98872026000801210
  21. Blood Adv. 2026 Oct 21. pii: bloodadvances.2026022085. [Epub ahead of print]
    Maintenance ALK inhibitor after hematopoietic cell transplantation in patients with anaplastic large cell lymphoma.
    Michelle Choe, Neel S Bhatt, Camille Keenan, Julie Rivers, Kasey J Leger, Katherine Tarlock, Jennifer J Wilkes, Corinne Summers, Marie Bleakley, Ann Dahlberg, Monica S Thakar.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2026022085
  22. Histopathology. 2026 Oct 18.
    Characterization of the morphological, immunophenotypical and cytogenetic features of high-grade B-cell lymphoma with 11q aberration.
    Zhihui Wang, Yi Liu, Jinghan Wang, Liming Xu, Han Zhang, Dan Li, Bo Wang, Lijun Wang, Zhaoming Wang, Wei Wang, L Jeffrey Medeiros, Fang Yu.
       AIMS: High-grade B-cell lymphoma with 11q aberration is a rare neoplasm of mature B-cell lineage, and large-scale clinicopathological studies of this disease remain scarce. To bridge this research gap, we conducted a retrospective analysis of HGBCL with 11q aberration, aiming to elucidate its pathogenesis, clinicopathological features and molecular profiles.
    METHODS AND RESULTS: By reviewing our hospital's case database from 2021 to 2025, we retrospectively screened 92 cases of high-grade or diffuse large B-cell lymphoma that had 11q fluorescence in situ hybridization (FISH) testing. Among them, 27 cases were confirmed to harbour 11q aberration and were enrolled in the present study. This cohort consisted of 24 males and 3 females with a median age of 61 years (range, 6-85). Eighteen (67%) patients presented with extranodal disease and nine (33%) had nodal disease. The gastrointestinal tract was the most commonly involved extranodal site (13 patients); two of these patients had concurrent lymph node involvement in the head and neck. Fourteen (52%) patients had advanced Ann Arbor stage (III, IV) disease. Eight (30%) patients had a history of immunocompromise including HIV infection, liver or kidney transplantation and other malignant tumours. The bone marrow was negative for lymphoma at initial diagnosis in all 21 patients assessed. Histologically, 20 (74%) cases had Burkitt-like or blastoid morphology and seven (26%) cases showed diffuse large B-cell-like morphology. Most cases (96%, 26/27) had a germinal centre B-cell immunophenotype. c-MYC was positive in all 26 tested cases and BCL2 was negative in 24 of 27 (89%) of cases. Mutational analysis was performed in 14 cases and potential driver mutations were identified in all involving 44 genes. The most frequently affected genes included TP53, IGLL5, DDX3X, BTG2, FOXO1, HIST1H1E and MYC. Following therapy, 24 patients achieved complete remission and disease-free survival. The prognosis was not related to the morphological features, Ann Arbor stage, co-occurrence of MYC aberrations or the chemotherapy regimens.
    CONCLUSIONS: High-grade B-cell lymphoma with 11q aberration may occur across all ages and confers a favourable prognosis. These tumours manifest morphological heterogeneity, and most cases display a Burkitt lymphoma-like immunophenotype characterized by CD10 positivity and BCL2 negativity. The most frequently mutated genes in our cohort are TP53, IGLL5, DDX3X, BTG2, FOXO1, HIST1H1E and MYC.
    Keywords:  11q aberration; B‐cell lymphoma; high‐grade
    DOI:  https://doi.org/10.1111/his.70303
  23. Hemasphere. 2026 Oct;10(10): e70507
    Newly diagnosed and relapsed follicular lymphoma: EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up.
    Marco Ladetto, Natacha Bolaños, Guy Bouguet, Klaus Herfarth, Wolfram Klapper, Sirpa Leppa, Kim Linton, Armando Lopez-Guillermo, Stefano Luminari, Franck Morschhauser, Jessica Okosun, Ewa Paszkiewicz-Kozik, Catherine Thieblemont, Sanne Helene Tonino, Marek Trneny, Judith Trotman, Umut Yilmaz, Martin Dreyling.
      Follicular lymphoma (FL) is the second most common lymphoma subtype in Europe, with a median age at diagnosis of 60-65 years. It is generally considered an indolent disease, and the median overall survival at diagnosis now likely exceeds 20 years. However, considerable heterogeneity exists. Diagnosis requires adequate biopsy material and a specialized hematopathologist. Staging and prognosis rely on positron emission tomography (PET)-computed tomography (CT). Prognostication at diagnosis is based on several validated clinical prognostic scores. Localized disease is usually treated with radiotherapy ± Rituximab. The treatment of disseminated disease includes active surveillance (or in selected cases Rituximab monotherapy) for low-tumor burden patients, and most often immunochemotherapy (or in selected cases chemo-free therapeutic options), ±antibody maintenance in high-tumor burden patients. For relapsed or refractory disease, treatment with Rituximab-Lenalidomide combination ± Tafasitamab or Epcoritamab from the first relapse and single-agent bispecific antibodies, chimeric antigen receptor T-cell therapy (CAR-T) cells, and Zanubrutinib-Obinutuzumab after second relapse should be prioritized over immunochemotherapy. Given the long natural history and risk of relapse, careful follow-up is an important part of patient management. Patients should be actively involved in decision-making. In this guideline, we present current evidence-based recommendations for diagnosis, staging, treatment, and follow-up.
    DOI:  https://doi.org/10.1002/hem3.70507
  24. Blood. 2026 Oct 23. pii: blood.2026033885. [Epub ahead of print]
    CD8 T-cell exhaustion linked with CAR T-cell failure can be mitigated by a non-alpha IL2 receptor agonist.
    Kotaro Arita, Enyu Dai, Xubin Li, Irtiza N Sheikh, Patrick K Reville, Jared Henderson, Ashley Lauren Wilson, Christan Dillard, Kevin Bowman, Haopeng Yang, Fuliang Chu, Robert Andrew Harkins, Nathan Michael Pate, Katie Malley, Dinesh S Bangari, Estela Rojas, Jason R Westin, Sairah Ahmed, Sattva S Neelapu, Francisco Vega, Rui Wang, Xiangming Li, Donald Shaffer, Linghua Wang, Michael R Green.
      Chimeric antigen receptor T-cell (CART19) therapy represents a breakthrough for relapsed or refractory large B-cell lymphoma (rrLBCL). However, suboptimal CART19 activity can lead to therapeutic failure and dismal outcomes. Through single cell RNA-sequencing of tumors at the time of progression from CART19, we show that a subset of tumor contain clonally expanded and proliferating populations of CART19 cells that acquire transcriptional features of dysfunction, suggestive of ongoing tumor cell engagement and chronic stimulation. Using an in vitro system to model this process, we show that iterative rechallenge of CART19 cells with target cells drives failure of tumor control associated with acquired transcriptomic features of T-cell dysfunction and reduced IL2 signaling. Pegenzileukin, a non-alpha IL2-receptor agonist, prevented CART19 dysfunction, improving T-cell expansion and tumor control in vitro. To test this concept in vivo, we developed a cell line model from a post-CART19 progression tumor that reproduces the response and failure kinetics observed in the originating patient. In vivo CART19 alone led to transient response followed by progression and secondary central nervous system relapse in this model, while the addition of pegenzileukin to CART19 led to the complete eradication of tumors. This provides mechanism-informed pre-clinical rationale for the use of non-alpha IL2 receptor agonists in combating T-cell exhaustion, a critical mechanism of CART19 failure.
    DOI:  https://doi.org/10.1182/blood.2026033885
  25. Front Med (Lausanne). 2026 ;13 1998014
    Case Report: Durable, well-tolerated complete response to epcoritamab plus pirtobrutinib in Richter transformation relapsing after CD19 CAR T-cell therapy.
    Ahmed Salleh Barefah.
      Richter transformation (RT) that relapses after CD19-directed chimeric antigen receptor (CAR) T-cell therapy has no established therapy and carries a dismal prognosis. We report an 84-year-old man with multiply relapsed, biopsy-proven diffuse large B-cell lymphoma-type RT and a high-risk MYC/BCL2 double-expressor phenotype who developed systemic relapse, with extensive osteolytic bone disease, after lisocabtagene maraleucel. Three cycles of atezolizumab produced no objective benefit. Treatment with epcoritamab, a CD3xCD20 bispecific antibody, plus pirtobrutinib, a non-covalent Bruton tyrosine kinase inhibitor, produced complete nodal metabolic resolution within 3 months that deepened to a complete metabolic response (Deauville score 2) by 10 treatment cycles, with resolution of two interim osteolytic lesions whose transient nature illustrates the interpretive challenges of PET/CT response assessment after cellular and T-cell-engaging therapies. The chemotherapy-free regimen was well tolerated at age 84, with no cytokine release syndrome, no neurotoxicity, and no cytopenias; the only toxicity was mild, reversible dexamethasone-related myopathy. The patient remains in ongoing clinical remission after approximately 10 months of therapy. This case extends the reported experience with epcoritamab plus pirtobrutinib specifically to the post-CAR T-cell relapse setting and suggests that this chemotherapy-free doublet may warrant consideration as a salvage strategy for older or frail patients with RT who are unfit for further cytotoxic therapy.
    Keywords:  Bruton tyrosine kinase inhibitor; CAR T-cell therapy; Richter transformation; bispecific antibody; chronic lymphocytic leukemia; diffuse large B-cell lymphoma; epcoritamab; pirtobrutinib
    DOI:  https://doi.org/10.3389/fmed.2026.1998014
  26. Leukemia. 2026 Oct 19.
    Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
    Xiqin Tong, Guopeng Chen, Yuzhe Pan, Yanling Chen, Yuxin Tan, Hongqiang Jiang, Qian Wang, Linlu Ma, Ruihang Li, Yuxing Liang, Xiaoyan Liu, Fuling Zhou.
      Acute myeloid leukaemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) frequently relapses after FLT3 tyrosine kinase inhibitor (TKI) therapy, highlighting the need to define mechanisms of drug tolerance. Here, we identify the mitochondrial complex I core subunit NDUFS2 as a determinant of FLT3 TKI tolerance in FLT3-ITD AML. A metabolism-focused CRISPR-Cas9 sensitiser screen, integrated with transcriptomic profiling of gilteritinib-resistant cells and primary samples, identified NDUFS2 as upregulated in acquired resistance and preferentially expressed in FLT3-ITD AML. NDUFS2 knockdown impaired complex I activity, oxidative phosphorylation, mitochondrial membrane potential and ATP production, thereby promoting apoptosis and sensitising FLT3-ITD AML cells to gilteritinib. Pharmacologic complex I inhibition with IACS-010759 similarly enhanced gilteritinib activity in FLT3-ITD AML cell lines and primary FLT3-ITD samples, activated AMPK-PERK-ATF4-CHOP stress signalling, promoted apoptosis, and reduced leukaemia burden in a patient-derived xenograft model. Genetic NDUFS2 knockdown also prolonged survival in a xenograft model. A preliminary murine safety assessment showed no overt toxicity under the tested short-term dosing schedule. These findings identify NDUFS2-dependent complex I activity as an adaptive metabolic dependency supporting FLT3 inhibitor tolerance and provide mechanistic insight for further preclinical evaluation.
    DOI:  https://doi.org/10.1038/s41375-026-03170-3
  27. Ann Hematol. 2026 Jul 24. pii: 471. [Epub ahead of print]105(11):
    Long-term hydroxyurea therapy alters bone marrow megakaryocyte morphology and associates with prognosis in myeloproliferative neoplasms.
    Zhikang Zheng, Yingqing Xu, Tian Zeng, Rumeng Li, Bingbing Wen, Qingmei Han, Xiaojing Bao, Jian Huang.
      Hydroxyurea (HU) is a first-line treatment for myeloproliferative neoplasms (MPNs), but a quantitative, standardized framework for assessing its impact on megakaryocyte (MK) morphology and prognosis remains lacking. This retrospective, two-center study analyzed 22,097 MKs from 280 patients (118 polycythemia vera [PV], 162 essential thrombocythemia [ET]), classified into 12 subtypes using the 5th edition WHO classification in conjunction with objectively derived thresholds (minimum P-value approach). Our primary contribution is to establish a quantifiable scoring framework that translates descriptive WHO categories into reproducible prognostic metrics. Using this framework, HU significantly reduced normal MK proportion in JAK2-ET (P = 0.0189), TN-ET (P = 0.0233), and JAK2-PV (P = 0.0427), while increasing abnormal subtypes (bulbous, separated nuclear MKs); conversely, IFN was associated with preserved normal MKs and reduced abnormal forms. Multivariate Cox regression, applied to our empirically derived cutoffs, identified protective thresholds (normal MK ≥ 58% in ET, ≥ 53% in PV; emperipolesis ≥ 2% in ET) and adverse cutoffs (Naked nuclei ≥ 13% in ET, ≥ 7% in PV; staghorn like ≥ 6% in ET; separated nuclear ≥ 3% in ET) for myelofibrosis progression (all P < 0.05). Our quantitative findings corroborate prior qualitative observations that long-term HU is associated with adverse MK remodeling, while IFN correlates with lower progression risk as captured by our threshold-based system. This standardized scoring approach-not the identification of new prognostic factors-provides a reproducible tool for monitoring treatment-related morphological changes and may inform risk-adapted therapy in MPN patients.
    Keywords:  Hydroxyurea; Interferon; Megakaryocyte morphology; Myeloproliferative neoplasms; Prognosis
    DOI:  https://doi.org/10.1007/s00277-026-07202-x
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