bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–10–26
24 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό



  1. Front Oncol. 2025 ;15 1669385
       Key point: IRM appears promising and well tolerated as first-line therapy for newly diagnosed PCNS DLBCL in a small pilot cohort; these hypothesis-generating results require confirmation in larger prospective studies.
    Background: Primary diffuse large B-cell lymphoma of the central nervous system (PCNS DLBCL) is a rare, aggressive lymphoma with rising incidence in elderly patients. Bruton tyrosine kinase (BTK) inhibitors show promise in recurrent/refractory cases, warranting exploration in newly diagnosed disease.
    Methods: This single-center pilot study evaluated the safety/efficacy of ibrutinib, rituximab, and high-dose methotrexate (IRM) in nine newly diagnosed PCNS DLBCL patients (2018-2019). Treatment included 4 cycles of IRM induction, consolidation (HSCT or 2 additional IRM cycles), and maintenance therapy (ibrutinib/lenalidomide).
    Results: After induction, overall response rate (ORR) was 100% (complete response [CR]: 77.8%, partial response [PR]: 22.2%). Post-consolidation, CR increased to 88.9%. At a median follow-up of 77.6 months, 5-year overall survival (OS) and progression-free survival (PFS) rates were both 77.8%, with 8 patients in sustained CR and one progression. No treatment-related deaths occurred; grade ≥3 adverse events were rare (2 neutropenia, 2 anemia, 1 gastrointestinal bleeding).
    Conclusion: In this small pilot cohort, IRM showed promising activity and tolerability as first-line therapy for PCNS DLBCL. These descriptive findings warrant confirmation in larger prospective trials (#ChiCTR1900027811).
    Keywords:  Bruton tyrosine kinase inhibitor; ibrutinib; methotrexate; newly diagnosed; primary diffuse large B-cell lymphoma of the CNS
    DOI:  https://doi.org/10.3389/fonc.2025.1669385
  2. Hemasphere. 2025 Oct;9(10): e70233
    EHA Guidelines Committee and the European MCL Network
      Mantle cell lymphoma (MCL) is a relatively rare B-cell lymphoma subtype, with a higher incidence among males and a median age of 70 years at diagnosis. MCL is characterized by clinically diverse behavior, from indolent disease to extremely aggressive, related to the presence of biological risk factors such as proliferation rate and TP53 mutations. Most often, patients present with disseminated disease, necessitating systemic treatment. Immunochemotherapy has historically been the mainstay of treatment, but recent data indicate that addition of novel agents, especially covalent Bruton tyrosine kinase inhibitors (cBTKi), may substantially improve outcome in younger and older patients, although a curative approach remains to be shown. In elderly patients, the standard of care is still immuno-chemotherapy such as rituximab-bendamustine, although this may be challenged by non-chemotherapeutic options, such as rituximab plus cBTKi. For patients with relapsed or refractory disease, treatment options are developing rapidly, including CAR-T cell therapy, novel BTK targeting agents, BCL2 inhibitors, and T-cell engagers. In this clinical practice guideline, we present current evidence-based recommendations for diagnosis, staging, treatment, and follow-up of MCL.
    DOI:  https://doi.org/10.1002/hem3.70233
  3. Blood Cancer J. 2025 Oct 21. 15(1): 169
      Baseline cytomolecular features and measurable residual disease (MRD) dynamics are both strongly prognostic in acute lymphoblastic leukemia (ALL). Whether early MRD response can overcome the adverse prognosis of high-risk (HR) cytomolecular features is largely unknown. We retrospectively identified 161 patients with newly diagnosed B-cell ALL who underwent MRD assessment with next-generation sequencing (NGS) for IG/TR rearrangements (sensitivity: 1 × 10-6). Early NGS MRD negativity (i.e. after 1 cycle of induction) was achieved in 33% of patients. Rates of NGS MRD negativity were similar in patients with standard-risk (SR) and HR cytomolecular features. Patients who achieved early NGS MRD negativity had the best outcomes (2-year relapse-free survival (RFS): 94% versus 66% if MRD-positive; P = 0.03). None of the 26 patients with early NGS MRD negativity subsequently relapsed. Early NGS MRD response also identified patients with HR Philadelphia-chromosome (Ph)-negative ALL with low risk of relapse and excellent long-term survival (2-year RFS: 100%); in contrast, the 2-year RFS was 38% for patients with HR ALL who remained MRD-positive after induction (P = 0.01). Outcomes remained poor for HR patients who achieved NGS MRD negativity at later timepoints. In a landmark analysis, allogeneic stem cell transplant (alloSCT) improved outcomes of patients with HR Ph-negative ALL who remained MRD-positive after induction (2-year RFS 80% versus 0% if no alloSCT; P = 0.009). In patients with B-cell ALL, achievement of early NGS MRD negativity is associated with durable remissions, regardless of baseline cytomolecular features. AlloSCT may improve outcomes of patients with HR ALL with suboptimal early MRD dynamics.
    DOI:  https://doi.org/10.1038/s41408-025-01373-y
  4. Discov Oncol. 2025 Oct 21. 16(1): 1944
       BACKGROUND: Chronic Myeloid Leukemia (CML) is a hematologic disorder depicted by BCR::ABL1 translocation; a constitutively active tyrosine kinase (TK) and a hallmark of CML. Kinase domain mutations and the activation of alternative signaling pathways lead to drug resistance in CML. TAM family kinases, including TYRO3 receptor tyrosine kinase (TYRO3-RTK), AXL receptor tyrosine kinase (AXL-RTK), and MER receptor tyrosine kinase (MERTK), are often overexpressed in various types of cancers. AXL-RTK plays a significant role in the survival of leukemic stem cells (LSCs) and provides adaptive resistance to CML cells against Tyrosine kinase inhibitors (TKIs). However, the specific functions and mechanisms of two other receptors, TYRO3-RTK and MERTK, in both sensitive and resistant CML cells are not yet documented. Therefore, this study aimed to explore the expression patterns and roles of TAM family kinases in sensitive and resistant CML.
    METHODS AND RESULTS: We have developed an Imatinib-Resistant CML model (K562-R) by administering an increasing dose of Imatinib over 4 months. Proliferation was evaluated through MTT assay. Apoptosis and expression analysis were conducted through the DNA fragmentation assay and RT-PCR, respectively. TYRO3-RTK, AXL-RTK, and MERTK were found to be 2, 7 and 25 folds higher in K562-R than K562-S cells respectively. Pharmacological targeting of TYRO3-RTK with LDC1267, AXL-RTK with R428, and MERTK with UNC2250 TAM inhibitors significantly interfered with the proliferation potential of both K562-S and K562-R cells. TAM kinase inhibitors also abridged colony formation in K562-S and K562-R cells. We have observed an additive antiproliferation effect by co-targeting TAM kinases with Imatinib in K562-S cells and a synergistic effect in K562-R cells. Mechanistically, apoptosis induction independent of p53, differential upregulation of cell cycle inhibitors, including p16, p21, and p27 in K562-S and K562-R cells were observed to be related with the proliferation inhibition. Furthermore, we showed that TAM family inhibitors interfere with the Wnt/β-catenin pathway by downregulation of downstream targets c-Myc, Axin2, its regulators, EYA3, and AXL-RTK in both K562-S and K562-R cells.
    CONCLUSION: TAM family kinase inhibitors significantly reduce the proliferation and colony formation of K562-S and K562-R cells by inducing apoptosis, interfering with Wnt/β catenin pathway, and upregulating cell cycle inhibitors.
    Keywords:  Cell cycle; Chronic myeloid leukemia (CML); K562-resistant (K562-R); K562-sensitive (K562-S); TAM family kinases; TAM kinase inhibitors; Wnt/β catenin pathway
    DOI:  https://doi.org/10.1007/s12672-025-03632-7
  5. Hematol Oncol. 2025 Nov;43(6): e70141
      Adult T-cell leukemia-lymphoma (ATL) is a rare, aggressive malignancy prevalent in Japan, the Caribbean, and Central/South America. This multicenter retrospective study evaluated the effectiveness and safety of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisolone (BV-CHP) in patients aged ≥ 18 years with previously untreated CD30-positive ATL, verified through immunohistochemistry/flow cytometry, from six hospitals in Japan. Outcomes included overall response rate (ORR; primary outcome), overall survival (OS), progression-free survival (PFS), complete response rate (CRR), disease control rate (DCR), and safety. Subgroup analyses evaluated lesion site, ATL subtype, age, and CD30 expression. Of 46 screened patients, 36 (median age 71 years; 66.7% female) were analyzed and started BV-CHP between April 2020 and January 2024. CD30 positivity was confirmed in all patients. ORR was 86.1% (95% confidence interval [CI] 70.5-95.3), CRR 61.1% (95% CI 43.5-76.9), and DCR 91.7% (95% CI 77.5-98.3). ORR by lesion site (lymph nodes, peripheral blood, skin) was 93.8%, 90.9%, and 83.3%, respectively, by ATL subtype (acute, lymphoma) was 78.9% and 94.1%, respectively, and by age (≤ 70 years, > 70 years) was 84.6% and 87.0%, respectively. One patient with CD30 expression < 10% achieved a complete response; ORR was 73.7% in 19 patients with CD30 expression ≥ 10%. Median OS and PFS was 535 days (95% CI 343-not estimable) and 205 days (95% CI 166-279), respectively. Treatment-emergent adverse events of any grade and grade ≥ 3 both occurred in 88.9% of patients, with neutropenia, febrile neutropenia, and thrombocytopenia being most common. Among 11 patients who underwent allogeneic stem cell transplantation, two developed acute graft-versus-host disease; median PFS was 234 days (95% CI 168-343), compared with 180 days (95% CI 96-279) without transplantation. BV-CHP demonstrated high ORR and CRR across age groups and ATL subtypes with a manageable safety profile, supporting its potential use as a standard treatment option.
    Keywords:  PTCL; adult T‐cell leukemia‐lymphoma; brentuximab vedotin; retrospective studies
    DOI:  https://doi.org/10.1002/hon.70141
  6. Blood. 2025 Oct 21. pii: blood.2025030559. [Epub ahead of print]
      GPRC5D has emerged as a promising therapeutic target in relapsed/refractory multiple myeloma (RRMM), particularly following progression after BCMA-directed CAR T-cell therapies. RD118 is a novel CAR T-cell therapy incorporating a fully human single-domain antibody fragment (VHH) targeting GPRC5D. In this phase 1 study, 18 relapsed/refractory patients (17 multiple myeloma, 1 with a history of primary plasma cell leukemia [pPCL]) received a single infusion of RD118 at 1.0, 2.0, or 3.0 × 106 CAR+ T cells/kg. At a median follow-up of 17.0 months, the overall response rate (ORR) was 94.4%, including 72.2% complete or stringent complete responses. Among seven patients previously exposed to BCMA-directed CAR T-cell therapy, ORR reached 85.7%. Median progression-free survival (PFS) was 18.2 months (95% CI, 14.4-not estimable), with 12-month PFS and overall survival (OS) rates of 82.1% and 93.3%, respectively. Cytokine release syndrome occurred in 88.9% of patients, primarily grade 1-2. One patient developed grade 3 immune effector cell-associated neurotoxicity which resolved within 72 hours. No cerebellar toxicities or treatment-related deaths were reported. These findings support that RD118 is a highly effective and safe therapeutic option for heavily pretreated RRMM. This trial is registered at ClinicalTrials.gov as NCT05759793 and NCT05219721.
    DOI:  https://doi.org/10.1182/blood.2025030559
  7. Clin Lymphoma Myeloma Leuk. 2025 Sep 19. pii: S2152-2650(25)04215-6. [Epub ahead of print]
      
    Keywords:  Dasatinib; Overall survival; Ph-like acute lymphoblastic leukemia; Ponatinib; Targeted therapy
    DOI:  https://doi.org/10.1016/j.clml.2025.09.010
  8. J Med Chem. 2025 Oct 25.
      Resistance to imatinib, a first-line BCR-ABL1 tyrosine kinase inhibitor for chronic myeloid leukemia, is frequently mediated by drug efflux through P-glycoprotein (P-gp) overexpression. We report the design, synthesis, and evaluation of eight novel imatinib derivatives modified at the piperazine terminus with efflux resistance breaker (ERB) fragments to reduce P-gp-mediated efflux. In silico docking against cryo-EM P-gp structures predicted increased hydrophobic interactions and enhanced occupancy at the access tunnel, indicative of efflux inhibition. Compound 8 showed potency comparable to imatinib in BCR-ABL1+ K562 cells and a lower LC50 fold change in resistant K562/DOX cells, suggesting reduced efflux susceptibility. Accumulation assays confirmed the improved intracellular retention of compound 8. Compound 9 displayed increased potency in resistant cells, correlating with higher intracellular levels despite modest kinase inhibition. Verapamil assays confirmed reduced efflux liability for compounds 8 and 13. Compound 8 also showed a positive therapeutic index. These findings support rational design to mitigate efflux-mediated resistance.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c01596
  9. Br J Haematol. 2025 Oct 23.
      The prognosis for patients with relapsed/refractory (R/R) adult T-cell leukaemia-lymphoma (ATL) remains dismal. Recently, valemetostat, a dual inhibitor for enhancer of zeste homologue (EZH) 1 and 2, was approved in Japan for R/R aggressive ATL. However, there is no real-world data on the efficacy and prognosis of valemetostat. We therefore analysed clinical outcomes in 28 patients with R/R aggressive ATL who received valemetostat at three hospitals in Kumamoto Prefecture between February 2023 and January 2025. The overall response rate (ORR) and complete response (CR) rate were 54.2% and 33.3% respectively. With a median follow-up of 19.2 months (7.3-21.7) for surviving patients, the median survival time was 15.8 months and median progression-free survival (PFS) was 8.3 months. The probabilities of 1-year overall survival (OS) and PFS were 55.8% and 44.1% respectively. Furthermore, the probabilities of 1-year duration of response and duration of CR were 56.2% and 71.4% respectively. Notably, the probability of 1-year OS was 90.9% in patients who achieved CR/partial response (PR) ('responders') compared to 17.0% in patients who did not achieve CR/PR (p < 0.001). Thus, valemetostat has the potential to be a reliable therapy for patients with R/R aggressive ATL, especially for responders.
    Keywords:  adult T‐cell leukaemia‐lymphoma; real‐world data; relapsed/refractory; valemetostat
    DOI:  https://doi.org/10.1111/bjh.70219
  10. Blood Adv. 2025 Oct 22. pii: bloodadvances.2025016727. [Epub ahead of print]
      Large B-cell lymphoma (LBCL) patients (pts) failing anti-CD19 Chimeric Antigen Receptor (CAR) T-cells therapy exhibit poor prognosis. Most progressions/relapses occur within 3 months from infusion while only a few events occur thereafter (late failure, LF). We analyze features, treatments and outcomes of pts with LF from DESCAR-T, a nationwide registry collecting real-life data for pts treated with approved CAR T-cell therapy in France. Between July 2018 and March 2024, 298 (39.9%) LBCL LF pts (median age 62 years, range 18-79, M 61.7%) were collected from DESCAR-T. Most pts had diffuse large B-cell lymphoma (DLBCL, n=205, 68.8%), advanced stage disease (84.6%) and age-adjusted International Prognostic Index (aaIPI) of 2-3 (59.3%) at CAR T eligibility. After failure, 76.5% pts received a systemic therapy and overall response rate (ORR) was 22.6% (complete response 18%). At a median follow-up since first late failure event of 13.8 (95% Confidence Interval [CI], 12.1-15.4) months, the median PFS-2 and OS-2 were 4.4 (95%CI, 3.8-5.8) and 13.2 (95% CI, 9.6-18) months, respectively. Compared to chemotherapy (HR=0.350, 95%CI, 0.193-0.633) and to pooled other treatments groups (HR=0.483, 95%CI, 0.290-0.805), salvage treatment with bispecific antibodies (BsAb) after CAR T failure showed better PFS-2. Radiotherapy obtained prolonged responses in some pts with 12-months PFS-2 of 41.5% (95%CI, 22.5-59.5). The present work is the first study describing LBCL pts with late failure after CAR T. BsAbs seem to be more effective compared to other strategies in LF setting and this should be considered in the design of new clinical trials.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016727
  11. Am J Hematol. 2025 Oct 22.
       DISEASE OVERVIEW: JAK2 unmutated erythrocytosis encompasses a heterogeneous spectrum of hereditary and acquired entities.
    DIAGNOSIS: The foremost step is excluding polycythemia vera (PV) with JAK2 mutation screening (exons 12-15). Apparent polycythemia such as physiological outliers or relative polycythemia secondary to volume contraction should be considered. A historical overview of hematocrit (Hct) and hemoglobin (Hgb) levels helps distinguish longstanding from acquired erythrocytosis. Serum erythropoietin (Epo) levels are variably informative.
    HEREDITARY ERYTHROCYTOSIS: Hereditary erythrocytosis should be considered in longstanding erythrocytosis with a positive family history; causes include EPOR mutations (subnormal Epo), high oxygen affinity hemoglobin variants, PIEZO1 mutations, 2,3-bisphosphoglycerate deficiency, methemoglobinemia, and germline oxygen sensing pathway mutations (HIF2A-PHD2-VHL).
    ACQUIRED ERYTHROCYTOSIS: Acquired erythrocytosis results from central (cardiopulmonary disease) or peripheral (renal artery stenosis) hypoxia, Epo-producing tumors (renal cell carcinoma) or drugs (testosterone, sodium glucose co-transporter-2 inhibitors (SGLT2-i), erythropoiesis stimulating agents).
    IDIOPATHIC ERYTHROCYTOSIS: Idiopathic erythrocytosis is an ill-defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology.
    MANAGEMENT: Cytoreductive therapy should be avoided. Phlebotomy should be considered for symptom control. Cardiovascular risk optimization and low-dose aspirin are advised, while the role of HIF2A inhibitors remains unclear.
    RECENT ADVANCES: EPO mutations which produce hyperactive, hepatic-like Epo were identified. In cases with negative workup but high clinical suspicion, an expanded next generation sequencing panel for hereditary erythrocytosis is recommended. Among drugs, SGLT2-i-associated erythrocytosis is increasingly recognized.
    FUTURE DIRECTIONS: Advances in molecular hematology are expected to improve the characterization of "idiopathic erythrocytosis". Results from prospective studies are needed to elucidate the underlying pathology and guide management.
    Keywords:  acquired; congenital; hereditary; polycythemia; secondary
    DOI:  https://doi.org/10.1002/ajh.70118
  12. Am J Hematol. 2025 Oct 24.
      Acute renal failure due to cast nephropathy (CAN) is a severe complication of multiple myeloma (MM). Here, we aimed to identify parameters associated with renal outcomes and survival in newly diagnosed MM patients with CAN-related acute renal failure and to validate the IMWG criteria for renal response. CAN diagnosis was based on biopsy or clinical assessment. Of 787 registered patients, 354 met the inclusion criteria, requiring at least two therapy cycles with documented chemotherapy response, renal response, and eGFR. Baseline free light chain (FLC) levels (median 6825.65 mg/L) decreased below 500 mg/L in 67.8% of patients. According to IMWG classification, renal complete response, partial response, and minimal response were achieved in 33.9%, 19.5%, and 28.0% of patients, respectively. The best eGFR values > 60 mL/min/1.73 m2 were observed in 33.9% of patients, while 33.3%, 22.3%, and 10.5% had best eGFR values of 30-59, 15-29, and < 15 mL/min/1.73 m2, respectively. Renal response correlated with baseline FLC levels, IgG kappa, eGFR, and ECOG status in multivariate analysis, as well as with myeloma response and FLC reduction in univariate analysis. Median overall survival was 77.6 months. Survival correlated with age, myeloma response, ECOG status, FLC kappa type, baseline eGFR, standard-risk cytogenetics, and calcium levels, among other factors. A comparison of IMWG renal response criteria with classification based solely on best eGFR showed similar utility. Of 136 patients requiring dialysis, 80 (58.8%) were able to discontinue dialysis during therapy. Bortezomib containing myeloma therapy, along with significant FLC reduction, was associated with favorable outcome.
    Keywords:  acute renal failure; cast nephropathy; multiple myeloma
    DOI:  https://doi.org/10.1002/ajh.70104
  13. Blood Adv. 2025 Oct 24. pii: bloodadvances.2025017755. [Epub ahead of print]
      CNS involvement (CNSi) of chronic lymphocytic leukemia (CLL) is a rare condition with no consensus on diagnosis and limited evidence for management and outcome. Here we report an international, multicenter, retrospective study conducted by the European Research Initiative on CLL (ERIC). The study defined CNSi of CLL by: 1) detection of CLL cells in the cerebrospinal fluid or confirmation of CLL infiltration of the CNS based on a tissue biopsy, 2) clinical or radiographic evidence of neurologic disease, and 3) the absence of other explanations for the neurologic findings. A total of 48 patients from 26 centers in 15 countries met all three diagnostic criteria of CLL-CNSi. Median age at diagnosis of CNSi was 64 years. Most patients were males (73%), had Binet stage A at CLL diagnosis (61%), and had untreated CLL at the time of CNSi (63%). Motor impairment was the most common symptom (38%) followed by visual impairment (32%). Of 47 patients who received treatment for CNSi, half (51%) received targeted agents, most commonly a BTK inhibitor (BTKi), and 34% received chemoimmunotherapy (CIT). Initial treatment was highly effective, leading to a reduction (83%) or complete resolution (71%) of neurologic symptoms and imaging findings in most patients. The estimated 5-year overall survival (OS) from the CNSi diagnosis was 77.1%. 5-year time-to-next-treatment or death was 94% for patients treated with BTKis compared to 64% for those treated with CIT. Treatment-sensitive disease, represented by attainment of CNS complete response after initial therapy, was associated with longer OS.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017755
  14. J Cell Mol Med. 2025 Oct;29(20): e70841
      Richter transformation (RT) is a serious complication of chronic lymphocytic leukaemia (CLL), with poor outcomes. While CAR T-cells have shown promise in large B-cell lymphoma, their efficacy in RT remains unclear, and the role of allogeneic stem cell transplant (alloSCT) post-CAR T-cells has not been established. This study aimed to assess the clinical response and survival of patients with RT treated with anti-CD19 CAR T-cells. This retrospective multicentre study, conducted by the European Research Initiative on CLL (ERIC), included patients with RT who received anti-CD19 CAR T-cells between 06/2018 and 01/2024. Progression-free survival (PFS) and overall survival (OS) were evaluated from CAR T-cell infusion. Fifty-four patients with RT were treated with anti-CD19 CAR T-cells (academic products, n = 29; commercial products, n = 25). The median age was 63 years, with 72% having an ECOG performance status (PS) of 0 to 1. Seven patients (13%) underwent alloSCT following CAR T-cell infusion, with the indications being consolidation therapy (n = 4) and relapse/progression (n = 3). The overall response rate was 65%, with 46% achieving complete response (CR) at 1 month and 50% at 3 months. The median PFS was 8.0 months (95% CI: 2.1-13.8) and the median OS was 14.4 months (95% CI: 8.8-19.2). The median PFS was 31.6 months for patients achieving CR at 1 or 3 months post CAR T-cells. Significant factors associated with mortality included high ECOG PS (p < 0.001), high LDH at CAR T infusion (p = 0.005), ICANS (p = 0.046) and no response at 1 month (p = 0.02). Multivariable Cox regression analysis identified treatment response at 1 month (p = 0.001) and increasing age (p = 0.5) as significant predictors of mortality. This study shows encouraging response rates and manageable toxicity for patients with RT treated with both academic and commercially available CAR T-cell products.
    Keywords:  CAR‐T cells; Richter transformation; allogeneic SCT
    DOI:  https://doi.org/10.1111/jcmm.70841
  15. Cancer Gene Ther. 2025 Oct 24.
      Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells. Minimal residual disease (MRD) assessment holds prognostic significance in both newly diagnosed and relapsed MM patients throughout the disease course. PCR-based targeted next-generation sequencing (NGS) methods face limitations in MRD monitoring due to somatic hypermutation (SHM) in MM. This study compares RNA-seq with the targeted IGH-CDR3-DNA-NGS method to identify more sensitive and convenient MRD monitoring techniques. We analyzed 125 samples from 35 MM patients and compared with 42 B-ALL patients, using MiXCR software for sequencing data processing. RNA-seq detected clonal immunoglobulin (IG) sequences in all bone marrow (BM) and peripheral blood (PB) initial samples with a sensitivity of 10-6, outperforming targeted-NGS, which missed some detections. The SHM rate was higher in targeted-NGS-negative samples (9.98%) compared to positive ones (7.27%). Clonal IG gene expression in MM was significantly higher than in B-ALL. Additionally, MRD-negative PB samples identified via RNA-seq and IG tag sequence correlated with improved survival. In conclusion, RNA-seq surpasses targeted-NGS in MRD monitoring for MM patients, providing comprehensive genetic information that aids in identifying specific IG gene expression patterns. Utilizing RNA-seq for MRD detection in PB samples effectively predicts prognosis.
    DOI:  https://doi.org/10.1038/s41417-025-00973-x
  16. Haematologica. 2025 Oct 23.
      Five hundred and thirty-five patients (median age 12.2 years, range: 8 months - 18 years; N=303 males, N=232 females) diagnosed with chronic myeloid leukaemia (CML) in chronic phase were registered in the International Registry of Childhood CML (www.clinicaltrials.gov NCT01281735). Clinical signs of leukostasis or bleeding were observed in 16.5% and 20% of the patients, respectively. The spleen was palpable in 76% of patients with a median of 9 cm (range, 1 to 32) below the costal margin. The median leukocyte count was 222 G/L (quartile 95-353). First-line therapy consisted of imatinib in 482 children. Among them, 40% remained on imatinib with a median follow-up 3.8 years (95% CI: 3.2-4.3 years); 3.1% died and 3.9% progressed to advanced phase disease. The overall survival rate at 36 months was 97.4% (95% CI: 95-99%). Progression free survival rate at 3-years was 97.1% (95% CI: 94.9-99.2%), 91.7% (95% CI:84.5-98.3%) and 72.0% (95% CI: 59-87.9%) in the Eutos Long Term Survival (ELTS) low, intermediate-, and high-risk group, respectively (p log rank.
    DOI:  https://doi.org/10.3324/haematol.2025.288283
  17. Blood. 2025 Oct 20. pii: blood.2024026749. [Epub ahead of print]
      Oncogenic growth places great strain and dependence on protein homeostasis (proteostasis). This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers at tolerable doses, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and increased autophagic flux to preserve proteostasis. Genetic inactivation of HSF1 sensitized AML cells to proteasome inhibition, marked by accumulation of unfolded protein, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival and significant slowing of disease progression and extension of survival in vivo. Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed human AML cells, and significantly reduced AML burden and extended survival in vivo. Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and colony formation, and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, compared to normal hematopoietic stem/progenitor cells. Combined autophagy/proteasome inhibition activated a terminal integrated stress response, which was surprisingly driven by Protein kinase R (PKR). These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.
    DOI:  https://doi.org/10.1182/blood.2024026749
  18. Biochem Pharmacol. 2025 Oct 22. pii: S0006-2952(25)00712-9. [Epub ahead of print] 117447
      Advanced extra-nodal natural killer/T-cell lymphoma (ENKTL) patients tend to be resistant to multiple chemotherapy drugs. Studies have shown that high expression of B-cell lymphoma 2 (BCL-2) is associated with poor prognosis and drug resistance of ENKTL, hence it is a potential therapy target. The BCL-2 homology (BH) domain 4 is essential for the anti-apoptotic function of BCL-2. Compared with BH3 domain, BH4 domain participates in more biological processes than just anti-apoptosis. Therefore, we tested the anti-tumor effect of BDA-366, a promising BCL-2 BH4 domain inhibitor, in treating ENKTL cells. The results showed that ENKTL cells were more sensitive to BDA-366 than other small-molecule inhibitors, such as ABT-199, S63845 and Chidamide. BDA-366 strongly induced apoptosis of ENKTL cells in vitro and significantly inhibited tumor growth in vivo with no obvious cytotoxicity to normal hematopoietic cells. Moreover, treatment with BDA-366 elevated reactive oxygen species (ROS) level and induced mitochondria damage in ENKTL cells, as evidenced by decreased mitochondrial membrane potential (MMP) and increased Ca2+ release. Gene Ontology (GO) enrichment analysis showed significant change of nuclear factor-kappaB (NF-κB) pathway in ENKTL cells treated with BDA-366, and by western blot, the expression of NF-κB p65 and mitochondrial function-related protein peroxisome proliferator-activated receptor γ coactivator-1β (PGC1β) were shown to be downregulated. In conclusion, as a BCL-2 BH4 domain antagonist, BDA-366 exhibited potent anti-tumor effect on ENKTL cells both in vitro and in vivo by triggering mitochondria-mediated apoptosis through suppressing NF-κB signaling pathway. Therefore, BDA-366 is a promising drug to treat ENKTL and overcome chemotherapy resistance.
    Keywords:  Apoptosis; BDA-366; ENKTL; NF-κB
    DOI:  https://doi.org/10.1016/j.bcp.2025.117447
  19. Br J Haematol. 2025 Oct 19.
      Marginal zone lymphoma (MZL) and Waldenström macroglobulinaemia (WM) are B-cell lymphomas characterized by an indolent disease course. However, both are incurable with current standard treatments. Therefore, additional therapies are certainly needed. BCL-2 inhibition has been a welcome addition to the treatment armamentarium for haematological malignancies. The BCL-2 inhibitor venetoclax is approved by the Food and Drug Administration and the European Medicines Agency for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia and is endorsed by the National Comprehensive Cancer Network for the treatment of WM and mantle cell lymphoma. In this review, we provide an overview of the current understanding of the BCL-2 apoptotic pathway and its impact on the development and maintenance of haematological cancers. We also summarize the preclinical and ongoing clinical experience with BCL-2 inhibitors, such as venetoclax, sonrotoclax, lisaftoclax and LOXO-338. BCL-2 inhibitors have emerged as safe and effective treatment options for treating patients with MZL and WM.
    Keywords:  BCL‐2 inhibitor; Waldenström macroglobulinaemia; apoptosis; lisaftoclax; marginal zone lymphoma; sonrotoclax; venetoclax
    DOI:  https://doi.org/10.1111/bjh.70208
  20. Eur J Nucl Med Mol Imaging. 2025 Oct 23.
       PURPOSE: Multiple myeloma (MM) frequently evades complete evaluation with 18 F-FDG-PET/CT due to variable hexokinase expression, leading to false-negative findings. 18 F-fluorocholine-PET/CT (FCH) targets membrane phospholipid synthesis and has been proposed as an alternative imaging strategy to address this limitation.
    METHODS: In this single-center retrospective study, 35 adult MM patients underwent dual-tracer PET/CT within four weeks. Lesions were scored using Deauville-based criteria (IMPeTUs), and exploratory composite scores (hTepe and myPET) were calculated. Laboratory markers, including M-protein, free light chains, and bone marrow infiltration, were collected within four weeks of imaging.
    RESULTS: The cohort (22 men, 13 women; mean age 62.2 ± 10.9 years) included 19 patients at initial staging and 16 at restaging. FDG detected active disease in 49% of patients, with 50.0% sensitivity and 100% positive predictive value (PPV). FCH identified disease in 91%, achieving 94.1% sensitivity and 100% PPV. Median bone marrow Deauville scores were similar (score-3), but FCH demonstrated significantly higher hypermetabolic focus scores (median 4 vs. 1; p < 0.001). FCH uptake moderately correlated with marrow plasma cell infiltration and inversely with hemoglobin and albumin, whereas FDG showed no consistent biochemical associations.
    CONCLUSION: FCH demonstrates superior diagnostic performance compared to FDG in MM, particularly in red marrow-rich regions. FCH more reliably reflects disease burden and aligns more closely with laboratory markers, supporting its role in staging, residual disease assessment, and treatment monitoring. Collectively, these results highlight FCH as a clinically applicable biomarker of disease burden with potential utility in routine staging and response evaluation in multiple myeloma.
    Keywords:  Choline; F-18 FCH PET/CT; F-18 FDG PET/CT; Hexokinase; Multiple myeloma; Plasma cell dyscrasias
    DOI:  https://doi.org/10.1007/s00259-025-07624-1
  21. Am J Med. 2025 Oct 16. pii: S0002-9343(25)00703-X. [Epub ahead of print]
       BACKGROUND: Erythrocytosis is common in daily clinical practice, and polycythaemia vera (PV), a myeloproliferative neoplasm associated with JAK2 mutations, should be systematically considered in clinical reasoning process. Financial constraints and environmental burden of extensive testing prompted us to develop a predictive score for PV to guide decision to screen for JAK2 mutations.
    METHODS: We retrospectively collected clinical and biological data from patients with PV and non-PV erythrocytosis who had low erythropoietin levels in 2024 at our hospital (derivation cohort). Data were analysed using univariable and multivariable methods to develop the TRAKJAK score, which was then validated in a separate cohort of patients referred to our centre in 2025 for erythrocytosis.
    RESULTS: We included 134 patients in derivation cohort (96 [72%] with PV and 38 [28%] without) and 65 in validation cohort (33 [51%] with PV and 32 [49%] without). The TRAKJAK score required at least one positive parameter among RBC count ≥6.57 × 1012/L, basophil count ≥0.1 × 109/L, and platelet count ≥300 × 109/L. In validation cohort, negative predictive value (NPV) was 96%, sensitivity was 97%, positive predictive value (PPV) was 82%, and specificity was 78%. In global cohort, sensitivity was 98%, specificity was 89%, PPV was 94%, and NPV was 95%, with a false negative rate of 1.5% and a false positive rate of 4.0%.
    CONCLUSION: Use of TRAKJAK could have prevented unnecessary JAK2 mutation screening in 62/70 patients (88%) who ultimately did not have PV. Like all clinical prediction tools, TRAKJAK is an aid to reduce over-investigation and must not replace clinical judgement.
    Keywords:  TRAKJAK; erythrocytosis; erythropoietin; jak2V617F; polycythemia vera
    DOI:  https://doi.org/10.1016/j.amjmed.2025.09.031