bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–08–10
sixteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Treatment-Free Remission in Chronic Phase Chronic Myeloid Leukemia After Nilotinib De-Escalation: 96-Week Update of the DANTE Study.
  2. Sustained MRD negativity: robust, not all-powerful.
  3. Frontline acalabrutinib, lenalidomide and rituximab for advanced stage follicular lymphoma with high tumor burden: phase II trial.
  4. Dose Optimization of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.
  5. How I Manage Chronic Myeloid Leukemia During Pregnancy.
  6. Myeloma: a sky full of MRD stars.
  7. New treatment strategies for primary central nervous system lymphoma.
  8. Value of serum-free light chain measurements in response and progression assessment in multiple myeloma with monoclonal protein measurable by electrophoresis.
  9. Durable outcomes with manageable safety leading to prolonged survival with tagraxofusp for treatment-naïve patients with blastic plasmacytoid dendritic cell neoplasm: real world results from a European Named Patient Program.
  10. Neutrophil-to-Lymphocyte ratio as surrogate for JAK2V617F suppression and event-free survival in polycythemia vera.
  11. Approach to hairy-cell leukemia in the new therapeutic era with special emphasis on age and comorbidities.
  12. CD24 senescent neutrophils as key players in myelofibrosis.
  13. Daratumumab for High-Risk Smoldering Multiple Myeloma.
  14. Anti-KIT antibody, briquilimab, induces mast cell apoptosis and depletion in non-human primates.
  15. [A new era in the treatment of myeloproliferative neoplasms].
  16. Where are the immunoglobulins? A review of non-secretory multiple myeloma.
  1. Hematol Oncol. 2025 Sep;43(5): e70126
    Treatment-Free Remission in Chronic Phase Chronic Myeloid Leukemia After Nilotinib De-Escalation: 96-Week Update of the DANTE Study.
    Alessandra Iurlo, Massimo Breccia, Fabio Stagno, Elisabetta Abruzzese, Fabrizio Pane, Immacolata Attolico, Paolo Sportoletti, Marco Cerrano, Sara Galimberti, Barbara Scappini, Maurizio Miglino, Sergio Siragusa, Isabella Capodanno, Diletta Valsecchi, Aurelio Pio Nardozza, Alessandra Misto, Paola Coco, Giuseppe Saglio, Gianantonio Rosti.
      Treatment-free remission (TFR) in chronic myeloid leukemia (CML) can be considered for patients in sustained deep molecular response (DMR) who can discontinue tyrosine kinase inhibitors (TKIs) while maintaining responses. Studies suggest that TKI de-escalation before TFR is feasible. This phase II study evaluated nilotinib de-escalation outcomes in adults with CML in chronic phase (CP) treated with first-line nilotinib for ≥ 3 years and in sustained DMR for ≥ 1 year. The study had four phases: screening, de-escalation (week 0-48), TFR (week 48-144) and follow-up. During de-escalation, patients received nilotinib 300 mg once daily, and those with sustained DMR entered TFR and discontinued nilotinib. Patients with major molecular response (MMR) but without sustained DMR continued nilotinib. At the data cut-off, 107 patients entered, and 98 (91.6%) completed de-escalation. TFR was entered by 90 patients (84.1%) with sustained DMR. At 96 weeks, 71/107 patients (66.4%) were in full TFR; 64/90 patients (71.1%) who entered TFR remained in ≥ MMR, and the median time-to-loss of MMR was not reached. During TFR, adverse events occurred in 64 patients (71.1%), including one serious event (pneumonia). Our data suggest that the de-escalation of nilotinib before a TFR attempt in CML-CP patients with sustained DMR can be a successful dose optimization strategy.
    Keywords:  chronic myeloid leukemia; nilotinib; sustained deep molecular response; treatment‐free remission
    DOI:  https://doi.org/10.1002/hon.70126
  2. Blood. 2025 Aug 07. 146(6): 652-653
    Sustained MRD negativity: robust, not all-powerful.
    Aurore Perrot, Jill Corre.
      
    DOI:  https://doi.org/10.1182/blood.2025029342
  3. Nat Commun. 2025 Aug 07. 16(1): 7300
    Frontline acalabrutinib, lenalidomide and rituximab for advanced stage follicular lymphoma with high tumor burden: phase II trial.
    Paolo Strati, Lei Feng, Jason R Westin, Ranjit Nair, Luis E Fayad, Maria A Rodriguez, Dai Chihara, Luis Malpica, Jared Henderson, Mariana Gallardo, Marissa Rivera, Iris Wang, Anastasiia Bolshakova, Anastasia Radko, David Kurtz, Stefan K Alig, Christopher R Flowers, Ash A Alizadeh, Sattva S Neelapu.
      This phase II trial aims to determine the efficacy and safety of frontline acalabrutinib, lenalidomide and rituximab for patients with advanced stage follicular lymphoma (FL) and high tumor burden. The primary endpoint was best complete response (CR) rate; the secondary endpoints were overall response rate (ORR), duration of response measured as CR at 30 months (CR30), progression of disease at 24 months (POD24) rate, progression-free survival (PFS), overall survival and safety. Twenty-four patients with previously untreated FL were included in this phase 2 single arm study (NCT04404088). The most common grade 3-4 adverse events were neutropenia (58%) and liver function test elevation (17%). Best ORR was 100% and best CR rate was 92%. CR30 rate was 65% and POD24 rate was 17%. After a median follow-up of 43 months, median PFS and OS were not reached, 2-year PFS rate was 79% and 2-year OS rate was 92%. Here we show that the addition of acalabrutinib to R2 is a safe and effective frontline regimen for FL patients, and further exploration in larger clinical trials is needed.
    DOI:  https://doi.org/10.1038/s41467-025-62509-z
  4. Clin Pharmacol. 2025 ;17 211-225
    Dose Optimization of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.
    Jiali Chen, Yidan Zhu, Yinyu Zhao, Nan Guo, Yuxuan Yao, Xingxian Luo, Lin Huang.
      With the advent of newer treatments such as new molecular targeted agents and immunotherapies, the model that selects therapeutic doses on the basis of the maximum tolerated dose is no longer relevant. The emergence of tyrosine kinase inhibitor (TKI) therapy has changed the treatment prospects for chronic myeloid leukemia (CML) and prolonged the long-term survival of CML patients. However, long-term exposure to TKIs is accompanied by adverse events, which may lead to disease progression and even death. It can also increase economic pressure on patients and affect their health-related quality of life. In general, dose reduction is feasible and safe for most patients and can reduce the incidence of adverse events while ensuring efficacy, reduce the financial burden on patients and society, improve the quality of life of patients, and also as a prelude to an attempt at treatment-free remission (TFR). This review will classify the dose optimization of all approved TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib, radotinib) at different stages of treatment based on clinical trials and real-life studies, including dose optimization prior to attempting TFR. In addition, we briefly describe the application of therapeutic drug monitoring in dose optimization and the potential benefits of dose optimization on health-related quality of life.
    Keywords:  chronic myeloid leukemia; dose optimization; therapeutic drug monitoring; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.2147/CPAA.S532263
  5. Blood. 2025 Aug 04. pii: blood.2024026513. [Epub ahead of print]
    How I Manage Chronic Myeloid Leukemia During Pregnancy.
    Elisabetta Abruzzese, Ekaterina Chelysheva.
      Chronic myeloid leukemia (CML) represents a paradigm of success in targeted therapy, with tyrosine kinase inhibitors (TKIs) revolutionizing patient outcomes. This progress has extended to the management of pregnancy in women with CML, a complex scenario requiring a balance between disease control and fetal safety. Since TKIs are contraindicated during the first trimester due to their teratogenic potential, treatment must be stopped as soon as pregnancy is confirmed, necessitating careful pre-conception planning and alternative management strategies. This article uses illustrative clinical cases to explore key aspects of CML pregnancy management, including the timing of TKI discontinuation, the feasibility of treatment-free remission, and the role of alternative therapies such as interferon-alpha. Additionally, we discuss the challenges of restarting treatment during pregnancy, the TKI selection in subsequent trimesters, and postpartum disease management, including breastfeeding considerations. Through the analysis of real-world cases, we provide insights into the evolving landscape of CML and pregnancy, offering practical guidance on optimizing maternal and fetal outcomes in this unique setting.
    DOI:  https://doi.org/10.1182/blood.2024026513
  6. Blood. 2025 Aug 07. 146(6): 649-650
    Myeloma: a sky full of MRD stars.
    Bruno Paiva, Jesús F San-Miguel.
      
    DOI:  https://doi.org/10.1182/blood.2025029160
  7. Curr Opin Oncol. 2025 Sep 01. 37(5): 414-423
    New treatment strategies for primary central nervous system lymphoma.
    Adrien Gilbert, Caroline Houillier, Carole Soussain.
       PURPOSE OF REVIEW: To summarize recent treatment strategies for primary central nervous system lymphoma (PCNSL) and present the new avenues for this rare and aggressive disease.
    RECENT FINDINGS: The current induction regimens based on high-dose methotrexate (HD-MTX) give similar and still insufficient response rates. Intensive consolidation with autologous stem cell transplantation has become the standard of care for eligible responder patients, while conventional whole brain radiotherapy has been abandoned due to irreversible treatment-related neurotoxicity. Maintenance treatment is being assessed for elderly and frail patients. Efforts are being made to improve the outcome after induction, mainly by adding targeted therapy to standard HD-MTX-based chemotherapy. A better understanding of PCNSL biology will optimize the use of targeted therapies based on the characteristics of the lymphoma cells and the tumor microenvironment. Preliminary results of chimeric antigen receptor T cells are encouraging. Cytokines or circulating tumor DNA are emerging as strong complementary tools to neuroimaging.
    SUMMARY: Outcome of fit patients has improved with intensive consolidation. New avenues include maintenance strategies for elderly and frail patients, targeted induction treatment, modern immunotherapies, and new drug-delivery modalities. Risk stratification and dynamic response assessment are necessary to design and evaluate personalized and response-driven treatment strategies.
    Keywords:  autologous stem cell transplantation; chimeric antigen receptor T-cell therapy; high-dose methotrexate; primary central nervous system lymphoma
    DOI:  https://doi.org/10.1097/CCO.0000000000001165
  8. Blood Cancer J. 2025 Aug 07. 15(1): 133
    Value of serum-free light chain measurements in response and progression assessment in multiple myeloma with monoclonal protein measurable by electrophoresis.
    Elham Askari, Angela Dispenzieri, Francis K Buadi, Suzanne R Hayman, Morie A Gertz, Prashant Kapoor, Wilson Gonsalves, Taxiarchis Kourelis, David Dingli, Rahma Warsame, Nelson Leung, Yi Lin, Eli Muchtar, Joselle Cook, Moritz Binder, Nadine Abdallah, Lisa Hwa, Miriam Hobbs, Amie Fonder, David Murray, Robert A Kyle, S Vincent Rajkumar, Shaji K Kumar.
      Uniform assessment of response to treatment is crucial to managing multiple myeloma (MM) and developing new therapies. Measurement of monoclonal protein forms the cornerstone of disease assessment in MM. According to International Myeloma Working Group (IMWG) guidelines, serum-free light chain (sFLC) is included in MM response assessment in patients with no measurable disease by electrophoresis and to define stringent complete response. We retrospectively analyzed the independent value of serial FLC on response and progression assessments in 839 patients with measurable disease by sFLC as well as serum/urine electrophoresis. A significant association was observed between sFLC and electrophoretic responses during initial therapy and at best response (p < 0.001). This study revealed comparable percentage changes in serial dFLC and urine M-protein, with parallel trends (p < 0.001) and strong correlations (r 0.55-0.79, p < 0.001). The response was detected earlier by sFLC (1.1 months, 95% CI 1.06-1.17), and sFLC ≥ PR after two cycles of induction demonstrated a strong predictive value for subsequent electrophoresis responses (OR 9.33, p < 0.001). Following induction, no difference in PFS was observed between very good partial response (VGPR) as determined by sFLC, sPEP, and uPEP (p = 0.538). The median second-PFS for patients with only sFLC-progression disease (PD) was similar to those with urine M-protein PD with or without sFLC-PD (HR 1.28, 95% CI 0.77-2.13, p 0.334). However, the median overall survival from the first relapse was significantly better for patients with only sFLC-PD (HR 1.87, 95% CI 1.07-3.27, p 0.03). Among patients with PD, 12% had sFLC as the only detectable tumor marker at the time of second-line therapy. This study supports the incorporation of serial sFLC measurements for monitoring response and progression in MM, even in patients with electrophoretic measurable disease, and further advocates replacing 24-h urine with serial sFLC in response assessment.
    DOI:  https://doi.org/10.1038/s41408-025-01340-7
  9. Ann Hematol. 2025 Aug 02.
    Durable outcomes with manageable safety leading to prolonged survival with tagraxofusp for treatment-naïve patients with blastic plasmacytoid dendritic cell neoplasm: real world results from a European Named Patient Program.
    Marco Herling, Emanuele Angelucci, Tobias Matthieu Benoit, Giulia Rivoli, Antonio Curti, Katharina S Götze, Stefan Wirths, Dimoula Erakli, Michael Zuurman, Eric Deconinck.
      Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive, poor-prognostic, and CD123-overexpressing orphan hematologic malignancy for which tagraxofusp, a CD123-targeted fusion protein, is the only approved drug. In this retrospective study, safety and efficacy of tagraxofusp were assessed through real-world clinical practice data, collected in patients with BPDCN who received tagraxofusp via a European Named Patient Program (2019-2024). Twenty-six adults with treatment-naïve BPDCN received 12 µg/kg tagraxofusp intravenously daily on days 1-5 (or by day 10) of a 21-day cycle. Primary endpoints were complete response (CR) rates and incidence/severity of capillary leak syndrome (CLS). Secondary endpoints included hematopoietic stem cell transplantation (HSCT), overall survival (OS), and safety. At a median follow-up of 13.5 months, the overall response rate (ORR) was 90% (65% CR); the median duration of response (DOR) was 10.3 months. In 12 evaluable patients who were bridged to HSCT, the pre-transplant ORR was 92% (75% CR), with 14.7 months median DOR. Median OS was 20.2 months (95% CI 10.2-not estimable) in the overall population and 37.0 months (95% CI 10.7-not estimable) in patients bridged to HSCT. CLS events were diagnosed in 13 patients (50%); 68% occurred in cycle 1; 54% were grade 2, and 46% grade 3/4. Treatment-related non-hematologic grade 3/4 adverse events (AEs) or serious AEs were reported in 12 patients (46%); 9 patients (35%) had treatment-related grade 3/4 hematologic AEs. These real-world findings showed no new safety signals and confirmed that tagraxofusp is the first-line treatment of choice for most patients with BPDCN.
    Keywords:  Acute myeloid malignancies; BPDCN; Biological therapy; CD123; Tagraxofusp
    DOI:  https://doi.org/10.1007/s00277-025-06493-w
  10. Blood Cancer J. 2025 Aug 06. 15(1): 132
    Neutrophil-to-Lymphocyte ratio as surrogate for JAK2V617F suppression and event-free survival in polycythemia vera.
    Tiziano Barbui, Arianna Ghirardi, Victoria Empson, Francesca Fenili, Giuseppe Gaetano Loscocco, Annalisa Condorelli, Alessandra Iurlo, Daniele Cattaneo, Elena Rossi, Valerio De Stefano, Paola Guglielmelli, Christoph Klade, Heinz Gisslinger, Alessandro Rambaldi, Joseph M Scandura, Alessandro Maria Vannucchi.
      Chronic systemic inflammation is a key driver of polycythemia vera (PV) progression, but the immunomodulatory effects of current treatments remain poorly defined. The neutrophil-to-lymphocyte ratio (NLR) is an accessible biomarker of systemic inflammation proven in other contexts, but its role in monitoring PV disease activity has not been established. Using data from three of the largest PV clinical trials, we evaluated the effects of PV therapies on NLR and its relationship with molecular response and clinical outcomes. In 404 hematocrit-controlled patients from the ECLAP study, hydroxyurea (HU) failed to significantly lower NLR (p = 0.11) due to the parallel declines in ANC and ALC. Neither leukocyte counts nor NLR were significantly reduced by phlebotomy in ECLAP patients treated without cytoreductive therapy. In contrast, the Low-PV study showed that while phlebotomy tended to increase NLR, low-dose ropeginterferon alfa-2b (Ropeg) significantly reduced NLR (-18.2% and -36.3% in patients with low and high baseline NLR, respectively) by suppressing ANC rather than lymphocytes. NLR reduction correlated with the primary Low-PV endpoint (p = 0.021) and reduction of JAK2 variant allele frequency (VAF) [1]. The PROUD-PV/CONTINUATION-PV study confirmed the superior effect of Ropeg over HU, with a significantly greater NLR reduction at 60 months (-56.5% versus -33.6%, respectively, p = 0.019) in patients with high baseline NLR. Moreover, NLR reduction was associated with decreased JAK2V617F VAF (p < 0.0001) and improved event-free survival (p = 0.010). These findings identify NLR as a dynamic biomarker of treatment response and prognosis in PV and support its incorporation into routine monitoring.
    DOI:  https://doi.org/10.1038/s41408-025-01317-6
  11. Acta Haematol. 2025 Aug 04. 1-19
    Approach to hairy-cell leukemia in the new therapeutic era with special emphasis on age and comorbidities.
    Ilana Levy Yurkovski, Tamar Tadmor.
      Hairy-cell leukemia (HCL) is a rare chronic hematologic malignancy, generally presenting with pancytopenia, relative lymphocytosis, monocytopenia, and splenomegaly. Diagnosis is based on typical bone marrow evaluation with the BRAF-V600E mutation being present in almost 100% of cases of classical HCL. Treatment usually involves the use of purine analogues (PA) as first line therapy. Novel targeting therapies have recently been included in the treatment of therapy-naïve HCL such as PA combination with anti-CD20, BRAF inhibitors alone or combined with anti-CD20. In relapse/refractory disease other novel agents were studied as BRAF and MEK inhibitors, Bruton tyrosine kinase or BCL2 inhibitors: all showed encouraging results. Most clinical trials and guidelines do not specify what is the optimal approach for patients with HCL in special situations as elderly population above 80 years old, very young patients below 40 years old, pregnant women, and when leukemia is presented with other comorbidities as active infection or vasculitis. In this current manuscript, we summarized our approach to HCL in the era of novel agents with special emphasis on age and comorbidities.
    DOI:  https://doi.org/10.1159/000547722
  12. Blood. 2025 Aug 07. 146(6): 653-655
    CD24 senescent neutrophils as key players in myelofibrosis.
    William Vainchenker, Nasrine Yahmi.
      
    DOI:  https://doi.org/10.1182/blood.2025029658
  13. N Engl J Med. 2025 Aug 07. pii: 10.1056/NEJMc2507790#sa1. [Epub ahead of print]393(6): 616-617
    Daratumumab for High-Risk Smoldering Multiple Myeloma.
    Surish P Shanmugam, Aya Awwad.
      
    DOI:  https://doi.org/10.1056/NEJMc2507790
  14. J Allergy Clin Immunol. 2025 Aug 01. pii: S0091-6749(25)00807-3. [Epub ahead of print]
    Anti-KIT antibody, briquilimab, induces mast cell apoptosis and depletion in non-human primates.
    Song Eun Lee, Hind Bouzid, Cheryl Kwan, Ajay Sharma, Andrea R Romo, Ruiqi Huang, Iris Zhan, Christopher Banfield, Jane R Parnes, Vaughn V Smider, Mang Yu, Hye-Sook Kwon, Wendy W Pang.
       BACKGROUND: Mast cells (MCs) play a critical role in many allergic and inflammatory reactions in healthy and disease states. Current therapeutic strategies to treat MC-mediated diseases aim to suppress MC activation by utilizing small molecule inhibitors or antibodies targeting specific signaling receptors on MCs. However, these strategies require chronic drug exposure, which have inherent limitations including increased patient burden and potential toxicity. Moreover, the redundancy between multiple signaling pathways concomitantly regulating MC activation can lead to insufficient MC suppression.
    OBJECTIVE: To develop a novel therapeutic strategy using an aglycosylated anti-KIT monoclonal antibody, briquilimab, to deplete MCs via KIT signaling inhibition.
    METHODS: Inhibition of KIT by briquilimab was evaluated in vitro in KIT expressing cell lines and primary human MCs. Briquilimab safety, pharmacokinetics, and MC depletion were evaluated in non-human primates (NHPs).
    RESULTS: Briquilimab potently blocks SCF ligand binding to KIT and inhibits SCF/KIT signaling and primary MC degranulation and survival, leading to MC apoptosis via PI3K/AKT pathway in vitro. Additionally, aglycosylation of briquilimab mitigates unwanted MC activation. In NHPs, single and multi-dose high, chronic exposure of briquilimab is well-tolerated with mild to moderate, but reversible adverse effects and effectively depletes various tissue MCs, such as lung, skin, and colon, in a dose-dependent manner.
    CONCLUSIONS: Briquilimab effectively inhibits SCF/KIT signaling and induces MC apoptosis, leading to profound and durable MC depletion in NHPs, and may provide a safe and novel therapeutic option to treat MC-mediated diseases.
    Keywords:  Briquilimab; KIT; mast cell; monoclonal antibody; stem cell factor
    DOI:  https://doi.org/10.1016/j.jaci.2025.07.019
  15. Rinsho Ketsueki. 2025 ;66(7): 597-610
    [A new era in the treatment of myeloproliferative neoplasms].
    Takuji Yamauchi.
      The treatment of myeloproliferative neoplasms (MPNs) has advanced significantly in recent years, leading to a reassessment of therapeutic strategies for polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). In PV, ropeginterferon alfa-2b has shown potential disease-modifying effects by reducing the JAK2 V617F allele burden. For ET, treatment remains focused on thrombosis prevention, with hydroxyurea as the mainstay, and novel agents such as pegylated interferon and bomedemstat (LSD1 inhibitor) are also under development. In MF, the evolution of JAK inhibitors is particularly noteworthy, with momelotinib and pacritinib showing potential benefits in alleviating anemia. Additionally, now that HemeSight® is covered by Japanese national health insurance, genetic mutation analysis has become more accessible, paving the way for risk classification based on genetic profiling. This review provides a comprehensive update on the latest risk stratification and therapeutic strategies for MPNs, highlighting emerging treatments and their potential impact on disease management.
    Keywords:  Genetics-based risk stratification; JAK inhibitor; JAK2 allele burden; MPN
    DOI:  https://doi.org/10.11406/rinketsu.66.597
  16. J Hematop. 2025 Aug 06. 18(1): 39
    Where are the immunoglobulins? A review of non-secretory multiple myeloma.
    Marcello Pecoraro Toscano, Megan O Nakashima.
      Multiple myeloma (MM) is a malignant neoplasm of clonal plasma cells, typically associated with the production of a monoclonal protein. In 1-3% of cases, MM presents without measurable monoclonal protein (M protein) in the serum or urine and normal serum-free light chains; these cases are referred to as non-secretory MM (NSMM). This definition has changed over time according to the sensitivity of laboratory methods for detecting paraproteins. NSMM has been previously reported to have a less aggressive presentation and clinical course compared to secretory MM; however, the literature is conflicting. Recent studies have indicated that NSMM may exhibit different responses to therapy and outcomes, emphasizing the need for a tailored approach. This review consolidates the current understanding of NSMM and underscores the importance of advanced diagnostic techniques in improving patient management and outcomes.
    Keywords:  M protein; Multiple myeloma; Non-producer myeloma; Non-secretory myeloma; Oligosecretory myeloma; Paraprotein; Plasma cell myeloma
    DOI:  https://doi.org/10.1007/s12308-025-00652-8
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