bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–10–19
forty-four papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Olverembatinib in accelerated-phase chronic myeloid leukemia: efficacy and safety evaluation.
  2. CD99 tunes translation to sustain stem cells.
  3. Unravelling a clinical role of peripheral blood leukemia stem cells at diagnosis in chronic myeloid leukemia patients: Final results of prospective FLOWERS study.
  4. Insights from Single-cell Omics: Cellular Heterogeneity as a Foundation of Clinical Outcome in Chronic Myeloid Leukemia.
  5. Dual Targeting of Smoothened, a Key Regulator in the Hedgehog Pathway, and BCR-ABL1 Effectively Eradicates Drug-Insensitive Stem/Progenitor Cells in Chronic Myeloid Leukemia.
  6. Ramantamig (JNJ-79635322), a novel T-cell-engaging trispecific antibody targeting BCMA, GPRC5D, and CD3, in multiple myeloma models.
  7. Primary CD34+ cells of patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome are highly sensitive to targeted treatment with TAK-243.
  8. Primary asciminib resistance in a chronic myeloid leukemia patient with the atypical BCR::ABL1 e13a3 transcript: a case study.
  9. Five-Year Follow-Up Analysis of ZUMA-5: Axicabtagene Ciloleucel in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma.
  10. Zataria multiflora extract enhances imatinib-induced cytotoxicity in chronic myeloid leukemia and multiple myeloma cells.
  11. Modulators of the Hepcidin Pathway in Polycythemia Vera and Myelofibrosis.
  12. Five-Year Follow-Up of Patients With Relapsed and Refractory Classic Hodgkin Lymphoma Treated With Low-Dose Nivolumab (40 mg): A Matched Cohort Study With Standard-Dose Therapy.
  13. Diagnostic sequencing identifies high-risk markers and mechanisms of resistance to guide immunotherapy selection.
  14. The emerging role of tafasitamab in follicular lymphoma.
  15. Incorporating Immunotherapy Into Upfront Acute Lymphoblastic Leukemia Therapy.
  16. Central nervous system myeloma: Pathogenesis, diagnostic challenges, and practical management strategies.
  17. Advances in the Diagnosis and Treatment of Myeloproliferative Neoplasms (MPNs).
  18. Enasidenib plus venetoclax in patients with IDH2-mutated relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome (ENAVEN-AML): a multicentre, single-arm, phase 1b/2 trial.
  19. How many NOTCHes (activation pathways) are there in CLL?
  20. The efficacy of varying doses of venetoclax combined with azacitidine for newly diagnosed adult acute myeloid leukemia in real-world settings: a single-center retrospective analysis.
  21. Diagnosis and Management of AML in Pediatric Patients: Consensus Recommendations from an International Expert Panel.
  22. Routine Imaging Surveillance After Frontline ABVD Improves Outcome in High-Risk Hodgkin Lymphoma.
  23. Rilzabrutinib and Bruton tyrosine kinase inhibition for the treatment of persistent or chronic immune thrombocytopenia.
  24. Orally available decitabine prodrug OR-2100 induces mitotic perturbation for the treatment of double-hit lymphoma.
  25. The Role of Radiation Therapy in the Management of Gray Zone Lymphoma.
  26. BCMA: BeCoMing a new hope for AL amyloidosis.
  27. Plain language summary of IMerge, a Phase 3 study of imetelstat versus placebo in people with lower-risk myelodysplastic syndromes and anemia.
  28. ID2 suppresses multiple myeloma cell proliferation by repressing the activity of the transcription factor TCF3.
  29. Impact of Dasatinib on Female Reproductive Health in Philadelphia-Positive Leukemia Patients.
  30. Heterozygous human JAK2V617F activates AhR to drive essential thrombocythemia and promote thrombosis.
  31. Accelerated In Silico Discovery of SGR-1505: A Potent MALT1 Allosteric Inhibitor for the Treatment of Mature B-Cell Malignancies.
  32. Turning Susceptibility into Strength: A New Era of Durable Resistance in Plants Through Genome Editing.
  33. Profound dFLC decrease after one cycle predicts superior outcome in patients with AL amyloidosis.
  34. Defying age: myth or reality?
  35. Prognostic impact of GNRI-IPI score in octogenarians with diffuse large B-Cell lymphoma treated with R-CHOP.
  36. Targeting PD-L1 for PCNS-DLBCL: from molecular effects to clinical translation.
  37. Zanubrutinib‑Induced Symmetrical Soft Tissue Forearm Swelling in a Patient With Waldenström Macroglobulinemia.
  38. Pentadecanoic Acid (C15:0) at Naturally Occurring Circulating Concentrations Has Selective Anticancer Activities Including Targeting B-Cell Lymphomas with CCND3 Oncogenic Alterations.
  39. MRD intervention in AML: A new therapeutic horizon.
  40. NR5A2 (located on chromosome 1q32) inhibits ferroptosis and promotes drug resistance by regulating phospholipid remodeling in multiple myeloma.
  41. Pediatric-inspired regimen abrogates the poor prognosis of adult early T-cell precursor acute lymphoblastic leukemia.
  42. Zanubrutinib is active for the treatment of relapsed primary vitreoretinal lymphoma.
  43. Results from a US modified Delphi consensus to define disease progression and disease modification in polycythemia Vera.
  44. Pulmonary toxicity induced by carfilzomib: a case report and review of the literature.
  1. Haematologica. 2025 Oct 16.
    Olverembatinib in accelerated-phase chronic myeloid leukemia: efficacy and safety evaluation.
    Mengyao Yuan, Li Zhou, Weiming Li, Xin Du, Jianyu Weng, Linhua Yang, Yanping Ma, Bingcheng Liu, Zhenfang Liu, Qin Wen, Shasha Zhao, Yanli Zhang, Qingxian Bai, Xianqi Feng, Yanqiu Han, Chunshui Liu, Li Meng, Baohong Wang, Xuehong Ran, Xiaodong Wang, Haiguo Zhang, Yun Zeng, Qing Leng, Lu Yu, Zongru Li, Robert Peter Gale, Xiaojun Huang, Qian Jiang.
      We studied 130 consecutive subjects who presented with (n = 29) or transformed to (n = 101) accelerated phase chronic myeloid leukemia (CML) and who received olverembatinib. 62 were in 2nd chronic phase. All failed ≥ 1 tyrosine kinase-inhibitors (TKIs) and 91 had BCR::ABL1T315I. Median follow-up was 28 months (InterQuartile Range, 10-74 months). The 6-year cumulative incidences of major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4.0 (MR4.0) were 59% (95% Confidence Interval [CI] (49, 69%), 53% (42, 62%), 52% (41, 62%) and 42% (31, 53%), respectively. The 6-year probabilities of transformation-free survival (TFS), CML-related survival and survival were 81% (72, 90%), 76% (67, 87%) and 71% (61, 82%), respectively. In multi-variable analyses, an interval from diagnosis of CML to olverembatinib start < 29 months, failure to achieve complete hematologic response (CHR) on prior TKI therapy, hemoglobin concentration < 98 g/L, blood and/or bone marrow blasts ≥ 8%, and/or high-risk additional chromosome abnormalities at the start of olverembatinib therapy, as well as not achieving early MCyR on olverembatinib correlated with worse outcomes. RUNX1 and STAT5A variants were significantly associated with worse TFS in the 82 subjects with targeted DNA sequencing data. There were acceptable treatment-related adverse events. We conclude olverembatinib is effective and tolerable in subjects in accelerated phase CML failing prior TKI therapy.
    DOI:  https://doi.org/10.3324/haematol.2025.288249
  2. Blood. 2025 Oct 16. 146(16): 1872-1873
    CD99 tunes translation to sustain stem cells.
    Kaosheng Lv, Wei Tong.
      
    DOI:  https://doi.org/10.1182/blood.2025030492
  3. Cancer. 2025 Oct 15. 131(20): e70122
    Unravelling a clinical role of peripheral blood leukemia stem cells at diagnosis in chronic myeloid leukemia patients: Final results of prospective FLOWERS study.
    Anna Sicuranza, Paola Pacelli, Adele Santoni, Elisabetta Abruzzese, Daniele Cattaneo, Alessandra Iurlo, Luigiana Luciano, Sara Galimberti, Valentina Giai, Olga Mulas, Giovanni Caocci, Federica Sorà, Isabella Capodanno, Monica Crugnola, Antonella Gozzini, Sabina Russo, Mario Annunziata, Claudio Fozza, Alessandra Cartocci, Sara Fredducci, Emanuele Pacini, Anna Marina Liberati, Marzia Defina, Elena Bestoso, Cristina Marzano, Dania Tocci, Teresa Miracapillo, Camilla Turriziani, Katia Peccia, Donatella Raspadori, Monica Bocchia.
       BACKGROUND: The authors previously demonstrated that in peripheral blood (PB) of chronic myeloid leukemia (CML), patients' leukemia stem cells (LSCs) CD26+ are detectable by flow cytometry at diagnosis, during tyrosine kinase inhibitor (TKI) therapy, and during treatment-free remission.
    METHODS: This study presents results of a prospective multicenter study including 242 newly diagnosed CML patients monitored for PB CD26+ leukemic stem cells (LSCs) quantification from diagnosis up to 24 months of TKI treatment.
    RESULTS: The bulk of CD26+ LSCs at diagnosis varied between patients with a median value of 7.14 cells/µL. During TKI treatment, it has been observed their consistent and rapid reduction without statistical differences according to type of first-line TKI. Instead, a significant correlation between a low amount of CD26+ LSCs at diagnosis and an optimal molecular response at 3, 12, and 24 months was documented (p = .03, p = .004, and p = .009, respectively). Three tertiles of CD26+ LSCs correlating to molecular response were identified: <3.21 cells/µL; between 3.21 and 19.21 cells/µL; and >19.21 cells/µL. The incidence of patients with optimal response was higher in the first CD26+ LSCs tertile respect to the third one (p = .027, p = .015, and p = .079, respectively) at all time points (3, 12 and 24 months).
    CONCLUSIONS: This study demonstrated a correlation between the amount of CD26+ LSCs at diagnosis and the molecular response, suggesting that the number of CD26+ LSCs at diagnosis could represent an additional tool for predicting TKI response.
    Keywords:  CD26; chronic myeloid leukemia; flow cytometry; leukemia stem cells; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1002/cncr.70122
  4. Blood. 2025 Oct 17. pii: blood.2025029011. [Epub ahead of print]
    Insights from Single-cell Omics: Cellular Heterogeneity as a Foundation of Clinical Outcome in Chronic Myeloid Leukemia.
    Ram Krishna Thakur, Göran Karlsson.
      The BCR::ABL1 tyrosine kinase inhibitors (TKIs) in CML represent a paradigm for molecularly targeted therapy. However, clinical outcomes - rate/depth of response, treatment-free remission (TFR), progression to blast crisis (BC) - and adverse events vary among patients. While additional somatic mutations have been invoked to explain varying clinical outcomes, we here propose a complementary perspective based on single-cell omics approaches that have enabled unprecedented resolution of the cellular ecosystems, including their composition, interactions, and activity. In treatment-naïve chronic phase (CP) patients, this has revealed differences in the growth-rate of BCR::ABL1+ clones, ratio of TKI-insensitive leukemic stem cells (LSCs) to residual hematopoietic stem cells (HSCs), and immune cell composition - factors that collectively contribute to variability in therapy efficacy. Together these findings suggest that cellular heterogeneity serves as a foundation of clinical outcome in CML. Patients who remain in CP exhibit an erythroid signature in LSCs, while those progressing to BC manifest an inflammatory profile, additional mutations, and expansion of early progenitors. Deep responders with active natural killer, and regulatory T-cells are more likely to sustain TFR. Similarly, the outcomes of donor lymphocyte infusion after allogenic stem cell transplantation are heterogenous and reflect differences in pre-existing T-cell clonotypes, their expansion and interaction with leukemic cells in responders versus non-responders. Here, we summarize key insights from sc-omics in CML and propose an actionable roadmap to further leverage these technologies. This includes mechanistically explaining heterogeneity, predicting therapy response and BC, tracking leukemogenic clones longitudinally, targeting TKI-insensitive LSCs, and restoring hematopoiesis from residual HSCs.
    DOI:  https://doi.org/10.1182/blood.2025029011
  5. Cells. 2025 Oct 09. pii: 1565. [Epub ahead of print]14(19):
    Dual Targeting of Smoothened, a Key Regulator in the Hedgehog Pathway, and BCR-ABL1 Effectively Eradicates Drug-Insensitive Stem/Progenitor Cells in Chronic Myeloid Leukemia.
    Kelly A Turner, Min Chen, Katharina Rothe, Donna L Forrest, Xiaoyan Jiang.
      Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. In particular, patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1 tyrosine kinase inhibitors (TKIs), partly due to a persistent population of TKI-resistant leukemic stem cells (LSCs). Therefore, identifying specific pathways crucial for LSC maintenance is necessary. The Hedgehog (HH) pathway, especially the protein Smoothened (SMO), has been found to be essential for CML LSCs, but its role in TKI resistance is still largely unknown. We have now demonstrated that the expression of HH pathway genes SMO and GLI2 is increased in CD34+ CML stem/progenitor cells compared to healthy counterparts, and is higher in TKI-nonresponders than in responders by transcriptome profiling and qRT-PCR analysis. Interestingly, they are most highly expressed in LSCs compared to progenitors and mature cells in TKI-nonresponders. Inhibition of SMO through genetic knockdown or with a potent, selective SMO inhibitor, Glasdegib, reduces the survival of cells from nonresponder patients. Notably, SMO inhibition also sensitizes TKI-nonresponder stem/progenitor cells to Bostutinib, a second-generation TKI, both in vitro and in a patient-derived xenotransplantation (PDX) model. These findings present a promising therapeutic target and a model for curative combination therapies in stem-cell-driven cancers.
    Keywords:  Bostutinib; Glasdegib (PF-04449913); Hedgehog pathway; Smoothened; chronic myeloid leukemia; leukemic stem cells; therapy-resistance; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.3390/cells14191565
  6. Blood. 2025 Oct 16. pii: blood.2025030027. [Epub ahead of print]
    Ramantamig (JNJ-79635322), a novel T-cell-engaging trispecific antibody targeting BCMA, GPRC5D, and CD3, in multiple myeloma models.
    Kodandaram Pillarisetti, Danlin Yang, Leopoldo Luistro, Jianhong Yao, Melissa Smith, Peter Vulfson, James Testa, Randolph Ponticiello, Scott R Brodeur, Bradley Heidrich, Kathryn Packman, Sanjaya Singh, Ricardo M Attar, Yusri A Elsayed, Ulrike Philippar.
      In multiple myeloma (MM), cell-specific antigens are valuable targets for developing effective T-cell-engaging therapeutics which could provide good immune responses. Achieving a sustained immune response in recurrent MM, however, remains challenging. Ramantamig (JNJ-79635322) is a trispecific antibody targeting B-cell maturation antigen (BCMA) and G-protein-coupled receptor class 5 member D (GPRC5D), both of which are highly expressed on plasmablasts and plasma cells in myeloma patient samples. Dual antigen recognition on malignant plasma cells by a trispecific T-cell engaging antibody could potentially enhance tumor binding through increased avidity, resulting in efficient depletion of the malignant clonal populations, targeting of tumor heterogeneity, and prevention of tumor antigen loss mediated resistance. At sub nM ranges, ramantamig induced potent cytotoxicity in cancer cell lines with concomitant T-cell activation. Ramantamig efficiently depleted both dual and single target-expressing MM cell lines. Additionally, it induced dose-dependent depletion of malignant plasma cells both in MM patient samples in an ex-vivo T-cell co-culture assay and in healthy fresh whole blood co-cultured with H929 MM cells to mimic physiological conditions. Ramantamig exhibited potent antitumor activity in a murine xenograft prevention model (single-target-expressing clonal cells) and two tumor regression models. The potent and selective antitumor activity of ramantamig, with a clonal depleting ability in vitro, ex vivo, and in vivo warrants clinical evaluation of its ability to induce durable responses in myeloma. Phase 1 clinical trials are ongoing for patients with relapsed/refractory MM (NCT05652335, NCT06768489).
    DOI:  https://doi.org/10.1182/blood.2025030027
  7. Br J Haematol. 2025 Oct 12.
    Primary CD34+ cells of patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome are highly sensitive to targeted treatment with TAK-243.
    Daniel Nowak, Marie Demmerle, Alessa Klär, Alexander Streuer, Vladimir Riabov, Eva Altrock, Felicitas Rapp, Ann-Christin Belzer, Teresa Klink, Meret Hahn, Franziska Hofmann, Verena Nowak, Nadine Weimer, Julia Obländer, Iris Palme, Melda Göl, Ali Darwich, Laurenz Steiner, Mohammed Abba, Georgia Metzgeroth, Wolf-Karsten Hofmann, Nanni Schmitt.
      
    Keywords:  MDS; TAK‐243; VEXAS syndrome; pevonedistat
    DOI:  https://doi.org/10.1111/bjh.70203
  8. Haematologica. 2025 Oct 16.
    Primary asciminib resistance in a chronic myeloid leukemia patient with the atypical BCR::ABL1 e13a3 transcript: a case study.
    Birte Kristin Jung, Sandra Weißmann, Caroline Schock, Manja Meggendorfer, Torsten Haferlach, Frank Dicker.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.288776
  9. J Clin Oncol. 2025 Oct 16. JCO2500668
    Five-Year Follow-Up Analysis of ZUMA-5: Axicabtagene Ciloleucel in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma.
    Sattva S Neelapu, Julio C Chavez, Alison R Sehgal, Narendranath Epperla, Matthew L Ulrickson, Emmanuel Bachy, Pashna N Munshi, Carla Casulo, David G Maloney, Sven de Vos, Ran Reshef, Lori A Leslie, Olalekan O Oluwole, Ibrahim Yakoub-Agha, Rashmi Khanal, Joseph D Rosenblatt, Jacob Wulff, Rhine R Shen, Wangshu Zhang, Soumya Poddar, Harry Miao, Olga Nikolajeva, Caron A Jacobson.
      Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Here, we report updated clinical outcomes from ZUMA-5 in 159 enrolled patients with R/R indolent non-Hodgkin lymphoma (iNHL; 127 with FL and 31 with marginal zone lymphoma) after a median follow-up of 64.6 months. Patients underwent leukapheresis and received lymphodepleting chemotherapy and axi-cel (2 × 106 CAR T cells/kg). The overall response rate was 90% (75% complete response rate). The median duration of response was 60.4 months, and the median progression-free survival (PFS) was 62.2 months; median time to next treatment and overall survival were not reached (NR). At data cutoff, 55% of patients were alive without requiring subsequent anticancer therapy. Median lymphoma-specific PFS in patients with FL was NR; 34% had progression or death due to lymphoma or study treatment. Notably, after 30 months postinfusion, progression or lymphoma-related deaths were rare. Late-onset toxicities were infrequent and largely unrelated to axi-cel. Durable response and prolonged survival in FL were associated with robust early CAR T-cell expansion and naïve product phenotype. These findings confirm sustained responses and manageable safety with axi-cel in the long term among patients with R/R iNHL and its potential as a curative therapy in FL.
    DOI:  https://doi.org/10.1200/JCO-25-00668
  10. Mol Biol Rep. 2025 Oct 14. 52(1): 1027
    Zataria multiflora extract enhances imatinib-induced cytotoxicity in chronic myeloid leukemia and multiple myeloma cells.
    Sahar Mostajeran, Mohsen Ehsan, Mahla Lashkari, Hajar Mardani Valandani, Ahmad Fatemi, Ali Bazi, Mahdieh Mirzaie, Muhammad Hossein Ashoub, Roohollah Mirzaee Khalilabadi.
       BACKGROUND: Zataria multiflora (ZM) is a medicinal plant with widespread antitumor effects. Tyrosine kinase inhibitors (TKIs) are considered the mainstay treatment in blood cancers; however, eventual resistance to TKIs poses a significant challenge in this area. The present study aimed to assess the synergistic effects of ZM extract (ZME) along with imatinib, a TKI, against K-562 and U-266 leukemic cell lines.
    METHODS: Cell viability was evaluated using the MTT assay, and apoptosis assessment was also conducted through Annexin-V/PI staining. Additionally, Real-Time PCR was used to assess the expression levels of BCR-ABL, P-TEN, c-MYC, Bax, and Bcl-2 genes. Molecular docking was carried out as an in-silico technique for both BCL-2 and ABL proteins.
    RESULTS: The results showed that both ZME and imatinib promoted apoptosis in K562 and U266 cells, with combination treatment significantly enhancing apoptotic cell death (e.g., 18.4% apoptosis in K562 cells with ZME + imatinib vs. 8.5% untreated; 46.9% in U266 cells vs. 11.6% untreated, P < 0.05). Combined treatment with imatinib and ZME upregulated the expression of Bax (5-fold in K562, 3-fold in U266) and P-TEN (2-fold in K562, 2.8-fold in U266) genes and downregulated the expression of Bcl-2 (0.3-fold in K562, 0.3-fold in U266), BCR-ABL (0.5-fold in K562), and c-MYC (0.4-fold in K562, 0.2-fold in U266) genes (P < 0.05). Molecular docking showed strong binding affinities between ZME constituents (carvacrol and thymol) and BCL-2 and ABL proteins.
    CONCLUSIONS: ZME shows potential as a complementary agent in vitro, warranting further investigation.
    Keywords:  Chronic myeloid leukemia; Imatinib; Multiple myeloma; Zataria multiflora
    DOI:  https://doi.org/10.1007/s11033-025-11106-w
  11. Blood. 2025 Oct 16. pii: blood.2025028643. [Epub ahead of print]
    Modulators of the Hepcidin Pathway in Polycythemia Vera and Myelofibrosis.
    Marina Kremyanskaya, Yelena Z Ginzburg, Ronald Hoffman.
      The peptide hepcidin is produced by the liver and serves as the central negative regulator of iron trafficking. Recently, drugs that affect the hepcidin pathway have been evaluated as potential treatment options for both controlling the degree of erythrocytosis in polycythemia vera (PV) patients as well as correcting anemia associated with myelofibrosis (MF). Under normal conditions, increased hepcidin levels limit iron absorption from the gastrointestinal tract and iron recycling from liver and splenic macrophages, thus decreasing plasma iron levels and restricting iron availability for erythropoiesis. In PV, however, unrestricted erythropoiesis occurs despite low systemic iron levels. Since hepcidin levels are relatively low in PV patients, hepcidin agonists (rusfertide, divesiran, sapablursen) are undergoing clinical development to control PV associated erythrocytosis, thereby reducing the need for therapeutic phlebotomies and myelosuppressive therapeutic options. By contrast, hepcidin levels are increased in MF patients leading to the trapping of iron in tissue macrophages which creates a picture which resembles the anemia of chronic inflammation. A number of strategies to lower hepcidin levels (the JAK2 inhibitors pacritinib and momelotinib, anti-hemojuvelin monoclonal antibody DISC-0974C) are currently undergoing clinical development to make systemic iron available for erythropoiesis and alleviate the degree of MF associated anemia. These new therapeutic options that modulate iron trafficking in PV and MF patients represent the application of greater knowledge of iron trafficking to create novel therapeutic options to treat patients with hematological malignancies.
    DOI:  https://doi.org/10.1182/blood.2025028643
  12. Hematol Oncol. 2025 Nov;43(6): e70146
    Five-Year Follow-Up of Patients With Relapsed and Refractory Classic Hodgkin Lymphoma Treated With Low-Dose Nivolumab (40 mg): A Matched Cohort Study With Standard-Dose Therapy.
    Liudmila Fedorova, Kirill Lepik, Polina Kotselyabina, Aminat Balaeva, Andrey Chekalov, Elena Kondakova, Ivan Moiseev, Natalia Mikhailova, Alexander Kulagin.
      The use of low-dose PD-1 inhibitors may offer a promising treatment strategy for patients with refractory Hodgkin lymphoma. This approach has the potential to mitigate the financial toxicity commonly associated with immune checkpoint inhibitors while also reducing the likelihood of severe adverse events. The aim of this study was to further investigate the efficacy and safety of nivolumab (nivo) at a 40 mg dose (LD group) within NCT03343665 clinical trial framework and to compare these results to the standard-dose therapy (SD group) using a propensity score matching approach. This study included 62 patients in each group. Median follow up was 63 (11-87) and 73 months (20-107) in the LD and SD group, respectively. The overall response rate and complete response was 68% and 39% versus. 70% and 39%, respectively. Five-year PFS was 26.8% (95% CI 17.8-40.7) and 22.1% (95% CI 12-40.6), p = 0.77, and 5-year OS 95.7% (95% CI: 90-100) and 93.3% (95% CI: 87-99), p = 0.33. The PFS was not statistically different regarding the prior treatment and key clinical factors. In the LD group the median dose of nivo was 0.58 mg/kg (0.35-0.91). There was no statistically significant difference based on dose per body weight in terms of survival. No differences were observed in the incidence of any AEs (69% vs. 77%) and 3-4 AEs (6% vs. 13%). Nivolumab therapy at a dose of 40 mg demonstrates comparable efficacy and safety to the standard dose of 3 mg/kg in patients with r/r cHL.
    Keywords:  PD‐1 inhibitors; checkpoint inhibitors; hodgkin lymphoma; low‐dose; nivolumab; nivolumab 40 mg; relapsed and refractory disease
    DOI:  https://doi.org/10.1002/hon.70146
  13. Blood Adv. 2025 Oct 15. pii: bloodadvances.2025017721. [Epub ahead of print]
    Diagnostic sequencing identifies high-risk markers and mechanisms of resistance to guide immunotherapy selection.
    Parvathi Sudha, Phillip Pham, Wen Niu, Enze Liu, Lin Wang, Gillian Truong, Cameron Ligocki, Ramzi Al-Azzawi, Mallini Surapenini, Steven Bray, Francesco Vetrini, Magdalena Czader, Marwan Tayeh, Kelvin P Lee, Rafat Abonour, Attaya Suvannasankha, Brian A Walker.
      Here we present the case for next generation sequencing of MM patient samples to not only identify high-risk markers, but also mutations and deletions relating to immunomodulatory drugs (IMiDs), and more importantly to guide the sequencing of immunotherapy regimens in response to intrinsic antigen escape as a means of treatment resistance and relapse. A single-center study of CD138+ cell selected samples (n=134) which included bone marrow aspirates from patients with smoldering multiple myeloma (n=11) and multiple myeloma (newly diagnosed n=38 and relapsed n=79) were sequenced using a targeted panel in a clinical diagnostics laboratory. Data were analyzed for high-risk markers, treatment related resistance mechanisms, and precision medicine targets to guide the future treatment of patients in the clinic. High-risk markers including t(4;14), t(14;16), t(14;20), gain or amplification 1q, deletion of CDKN2C, and deletion or mutation of TP53 were identified in 15% of newly diagnosed myeloma patient samples. At relapse, alterations in the cereblon degradation pathway were found in 24.3% of IMiD treated patients. Deletions of 4p (CD38) were also enriched in patients who received anti-CD38 treatment (P=0.03) which were mostly monoallelic. Deletions and mutations were detected in TNFRSF17 encoding BCMA in patients treated with anti-BCMA regimens, and the information was used to change the treatment of the patients. Targeted sequencing of multiple myeloma patient diagnostic samples can be used for risk stratification and also to monitor and adjust treatments as resistance mechanisms evolve.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017721
  14. Leuk Lymphoma. 2025 Oct 15. 1-10
    The emerging role of tafasitamab in follicular lymphoma.
    Tanja Lazic, Emiliano Barbieri, Stefano Luminari.
      Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma, characterized by recurrent relapses, risk of histologic transformation, and heterogeneous clinical outcomes. Despite advances with novel therapies, the management of relapsed/refractory FL remains challenging. Tafasitamab, a humanized anti-CD19 monoclonal antibody, is currently approved, in combination with lenalidomide, for relapsed refractory (R/R) diffuse large B-cell lymphoma (DLBCL), and together with lenalidomide and rituximab for R/R FL. Clinical trial data support its efficacy and manageable safety profile in FL starting from fisrt relapse, including in high-risk FL subgroups such as early relapse (POD24) and CD20-refractory disease. This chemotherapy-free regiment is added with its favorable safety profile to more complex therapies such as CAR T-cell therapy or bispecific antibodies. Further studies are needed to clarify tafasitamab's durability of benefit, optimal sequencing, and integration within the evolving FL treatment landscape.
    Keywords:  POD24; Tafasitamab; follicular lymphoma; immunotherapy; non-hodgkin lymphoma
    DOI:  https://doi.org/10.1080/10428194.2025.2560083
  15. Clin Lymphoma Myeloma Leuk. 2025 Sep 11. pii: S2152-2650(25)04201-6. [Epub ahead of print]
    Incorporating Immunotherapy Into Upfront Acute Lymphoblastic Leukemia Therapy.
    Ajoy L Dias, Mark R Litzow.
      Immunotherapy has transformed the treatment of acute lymphoblastic leukemia (ALL) over the past 2 decades with excellent outcomes in both adults and children particularly in the relapsed/refractory (R/R) disease setting where in general the treatment outcomes are dismal. Several immune therapies including monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, and chimeric antigen receptor T-cells have shown excellent outcomes and safety in this setting. Based on the observed high response rates and improved survival outcomes in patients with R/R ALL, immunotherapy is now being prospectively studied in the upfront setting with an aim to reduce treatment related toxicity and death with conventional chemotherapy. In this manuscript we discuss the various clinical trials that have shown excellent outcomes in the frontline setting and discuss how best to incorporate them in newly diagnosed, treatment naïve ALL patients either as monotherapy or in combination with cytotoxic agents.
    Keywords:  Blinatumomab; Chemotherapy-free; Chimeric antigen receptor therapy (CAR-T therapy); Inotuzumab ozogamicin; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.clml.2025.09.008
  16. Hemasphere. 2025 Oct;9(10): e70213
    Central nervous system myeloma: Pathogenesis, diagnostic challenges, and practical management strategies.
    Eirini Katodritou, Evangelos Terpos.
      Central nervous system multiple myeloma (CNS-MM) is a rare and aggressive extramedullary manifestation of multiple myeloma, associated with poor prognosis and significant treatment challenges. Due to its rarity, data on incidence, risk factors, optimal therapeutic approaches, and long-term outcomes remain limited. This review aims to elucidate the current diagnostic and therapeutic challenges of CNS-MM and provide practical insights into real-life management strategies.
    DOI:  https://doi.org/10.1002/hem3.70213
  17. Cancers (Basel). 2025 Sep 27. pii: 3142. [Epub ahead of print]17(19):
    Advances in the Diagnosis and Treatment of Myeloproliferative Neoplasms (MPNs).
    Xinyu Ma, Zhibo Zhou, Shuyu Gu, Yan Guo, Tianqing Zhou, Ruonan Shao, Jinsong Yan, Wei Chen, Xiaofeng Shi.
      Myeloproliferative neoplasms (MPNs) encompass three principal subtypes: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These hematologic malignancies originate from clonal hematopoietic stem cells (HSCs) and exhibit pathological overproduction of myeloid lineage cells. Recent advances in molecular diagnostics, particularly the precise detection of core driver mutations (JAK2 V617F, CALR, and MPL) and non-driver mutations (ASXL1, TET2, SRSF2), has refined diagnostic precision and risk stratification. A variety of prognostic models for MPNs provide guidance for treatment. Treatment methods mainly include bloodletting therapy, low-dose aspirin anticoagulant therapy, cytoreductive therapy, and allogeneic hematopoietic stem cell transplantation (HSCT). JAK inhibitors (such as ruxolitinib) remain the basic therapeutic drugs. However, emerging strategies targeting epigenetic dysregulation and the interaction in the immune microenvironment (such as interferon-α) show promise in reducing drug resistance. New methods, including combination therapy (combination of JAK inhibitors and BCL-XL inhibitors) and mutation-independent immunotherapy, are under investigation. This review summarizes the latest advancements in the diagnosis and treatment of MPNs, highlighting the importance of molecular mechanisms in guiding therapeutic approaches and the potential for precision medicine in the future.
    Keywords:  challenges and future directions; diagnosis and treatment; driver mutations; essential thrombocythemia (ET); myeloproliferative neoplasms (MPNs); polycythemia vera (PV); primary myelofibrosis (PMF); risk stratification
    DOI:  https://doi.org/10.3390/cancers17193142
  18. Lancet Haematol. 2025 Oct 08. pii: S2352-3026(25)00254-6. [Epub ahead of print]
    Enasidenib plus venetoclax in patients with IDH2-mutated relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome (ENAVEN-AML): a multicentre, single-arm, phase 1b/2 trial.
    Guillaume Richard-Carpentier, Gopila Gupta, Charina Koraksic, Severine Cathelin, Lisa Wang, Aniket Bankar, Marta Davidson, Vikas Gupta, Dawn Maze, Mark D Minden, Tracy Murphy, Aaron D Schimmer, Andre C Schuh, Hassan Sibai, Karen Yee, Courtney D DiNardo, Joseph Brandwein, Caroline J McNamara, Steven M Chan.
       BACKGROUND: Enasidenib, a mutant IDH2 inhibitor, is used to treat IDH2-mutated acute myeloid leukaemia (AML). Preclinical studies have demonstrated synergy between enasidenib and venetoclax, a BCL2 inhibitor, in IDH2-mutated AML. The aim of this study was to evaluate the safety and activity of enasidenib plus venetoclax in patients with relapsed or refractory IDH2-mutated AML or myelodysplastic syndromes (MDS).
    METHODS: The ENAVEN-AML study was a single-arm, phase 1b/2 trial conducted at two centres in Canada. Patients were eligible to participate if they were 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 to 2, had a confirmed IDH2 mutation (affecting Arg140 or Arg172), and had AML or MDS that was refractory or had relapsed after at least one line of treatment. Patients were treated with venetoclax 400 mg orally daily with a 3-day dose ramp-up starting on cycle 1 day 1 and enasidenib 100 mg orally daily starting on cycle 1 day 15. The primary endpoint of the phase 1b portion was safety, which included dose-limiting toxicity and the frequency and severity of treatment-emergent adverse events (TEAEs), as well as determining the maximum tolerated dose and recommended phase 2 dose. The primary objective of the phase 2 portion was to assess preliminary activity, with overall response rate by intention-to-treat as the primary endpoint. Assessment of safety and activity were determined on the pooled analysis data from the phase 1 and 2 studies. The ENAVEN-AML study is registered with ClinicalTrials.gov (NCT04092179) and is completed.
    FINDINGS: From Nov 12, 2020, to July 5, 2022, the study enrolled 27 patients (13 in phase 1b, 14 in phase 2) and the median follow-up was 20·2 months (IQR 15·0-23·0) at the data cutoff on Sept 30, 2023. The median age was 70 years (IQR 55-76); 16 (59%) of 27 patients were male, 11 (41%) female, and 19 (70%) White. 26 patients had relapsed or refractory AML, and one patient had relapsed MDS. The most common grade 3 or worse TEAEs were febrile neutropenia (n=11, 41%), infections (n=8, 30%), thrombocytopenia (n=7, 26%), pneumonia (n=6, 22%), sepsis (n=5, 19%), and anaemia (n=5, 19%). One case of IDH inhibitor-associated differentiation syndrome was observed. Serious adverse events were reported in 17 (62%) of 27 patients, most commonly infections (n=11, 41%) and intracranial bleeding (n=5, 19%). No dose-limiting toxicities or treatment-related deaths were observed. The recommended phase 2 dose was 400 mg daily for venetoclax and 100 mg daily for enasidenib. Of the 26 patients with AML, the overall response rate was 62% (95% CI 41-80; 16 of 26), with 13 (50%) of 26 having complete remission. The only patient with MDS did not respond to enasidenib plus venetoclax.
    INTERPRETATION: Enasidenib plus venetoclax is safe, with no unexpected TEAEs or treatment-related deaths, and shows preliminary activity in patients with relapsed or refractory IDH2-mutated AML and MDS.
    FUNDING: AbbVie and Bristol Myers Squibb.
    DOI:  https://doi.org/10.1016/S2352-3026(25)00254-6
  19. Blood. 2025 Oct 16. 146(16): 1876-1877
    How many NOTCHes (activation pathways) are there in CLL?
    Federico Pozzo, Valter Gattei.
      
    DOI:  https://doi.org/10.1182/blood.2025030461
  20. Hematology. 2025 Dec;30(1): 2571248
    The efficacy of varying doses of venetoclax combined with azacitidine for newly diagnosed adult acute myeloid leukemia in real-world settings: a single-center retrospective analysis.
    Yanjie Mao, Yifeng Cai, Yanan Wu, Tianzhi Wang, Yaping Zhang, Xi Yang, Hong Liu, Li Yang, Yingxin Sun.
       INTRODUCTION: The combination of venetoclax and azacitidine shows significant efficacy in newly diagnosed acute myeloid leukemia (ndAML) patients. In specific contexts, low-dose venetoclax may be preferred to optimize patient tolerance.
    METHOD: The study included 64 adult ndAML patients treated at the Affiliated Hospital of Nantong University between April 1, 2021, and April 30, 2024, investigated the efficacy and outcomes of standard-dose versus reduced-dose venetoclax in combination with azacitidine for induction chemotherapy in adult ndAML patients.
    RESULTS: The analysis found no significant difference in composite complete remission (CRc) rates after the first cycle between groups; however, the median event-free survival (EFS) (P = 0.006) and overall survival (OS) (P = 0.014) were markedly shorter in the reduced-dose cohort. Additionally, validation analysis of the 2024 LeukemiaNet (ELN) risk classification revealed a noteworthy distinction in OS among patients with distinct risk classifications receiving reduced-dose venetoclax plus azacitidine (P = 0.048).
    CONCLUSION: These findings suggest that while both dosing strategies may yield comparable initial responses, long-term outcomes could be adversely influenced by dose reduction, and the 2024 ELN risk classification is more suitable for adult patients with ndAML receiving a reduced-dose regimen of venetoclax and azacitidine.
    Keywords:  Acute myeloid leukemia; azacitidine; efficacy; prognosis; venetoclax
    DOI:  https://doi.org/10.1080/16078454.2025.2571248
  21. Blood. 2025 Oct 17. pii: blood.2024027904. [Epub ahead of print]
    Diagnosis and Management of AML in Pediatric Patients: Consensus Recommendations from an International Expert Panel.
    C Michel Zwaan, Sarah K Tasian, Richard Aplenc, Lisa Eidenschink Brodersen, Barbara Buldini, Barbara De Moerloose, Michael N Dworzak, Linda Fogelstrand, Brenda Es Gibson, Bianca F Goemans, Henrik Hasle, Betsy A Hirsch, Gertjan Jl Kaspers, Jan-Henning Klusmann, Matthew A Kutny, Thomas Lehrnbecher, Franco Locatelli, Shoeil Meshinchi, Arnaud Petit, Martina Pigazzi, Anne Tierens, E Anders Kolb, Dirk Reinhardt, Daisuke Tomizawa, Todd M Cooper.
      The European LeukemiaNet has periodically issued guidelines for the diagnosis and management of acute myeloid leukemia (AML) in adults. These consensus recommendations, most recently updated in 2022, incorporate recent advances in genomic testing, disease detection methods, target identification, and response assessment. Whilst similarities exist between AML in children and adults, pediatric AML is frequently characterized by unique cytogenetic and molecular features, which require distinct genetic and immunophenotypic diagnostics, therapeutic approaches, response assessment criteria, and supportive care strategies. To address these specific needs, an international panel of pediatric hematologist-oncologists, biologists, geneticists, and laboratory medicine scientists convened to develop recommendations for the diagnosis and management of AML in children, adolescents, and young adults (hereafter termed pediatric AML) that are discussed in this special report.
    DOI:  https://doi.org/10.1182/blood.2024027904
  22. Cancers (Basel). 2025 Oct 06. pii: 3242. [Epub ahead of print]17(19):
    Routine Imaging Surveillance After Frontline ABVD Improves Outcome in High-Risk Hodgkin Lymphoma.
    Novella Pugliese, Marco Picardi, Annamaria Vincenzi, Claudia Giordano, Anna Lucania, Alessandro Severino, Claudia Salvatore, Massimo Mascolo, Paola Della Cioppa, Fabrizio Pane.
      Background/Objectives: Despite the high complete response (CR) rate to first-line therapy, approximately one-third of patients with advanced-stage Hodgkin lymphoma (HL) eventually relapse. In up to 30-50% of cases, relapses are subclinical, i.e., initially detected only by imaging procedures. However, there is no definitive consensus on the optimal surveillance strategy for high-risk HL patients. Methods: The purpose of this cohort study is to evaluate the long-term outcome of stage II-B/IV HL patients who relapsed under routine imaging surveillance (imaging cohort) compared to those who relapsed under conventional clinical monitoring (standard cohort). Follow-up in the imaging cohort systematically included FDG-PET/CT, ultrasonography, and/or chest X-ray. At relapse, patients were treated with the same approach (salvage therapy and autologous hematopoietic stem cell transplantation [AHSCT]) in both cohorts. Results: A total of 123 high-risk HL patients were assessed at their first relapse: 80 in the imaging cohort and 43 in the standard cohort. The 2-year event-free survival (EFS) was significantly higher in the imaging cohort compared to the standard cohort (70% vs. 37.2%, respectively; p = 0.001). Similarly, the CR rate following salvage treatment was greater in the imaging cohort as compared to the standard cohort (68.8% vs. 41.9%, respectively; p < 0.004). These differences were due to the capability of routine imaging surveillance to detect disease with more limited extension (early onset of clinically silent relapses) as compared to standard clinical monitoring, which was associated with relapsed disease in a more advanced stage. Conclusions: Our findings suggest that routine imaging surveillance in patients with high-risk HL leads to improved EFS detecting relapses, which were characterized by more favorable prognostic factors (low tumor burden), thus enabling the timely administration of salvage therapy.
    Keywords:  Hodgkin lymphoma; first relapse; follow-up; post-recurrence survival
    DOI:  https://doi.org/10.3390/cancers17193242
  23. Expert Opin Pharmacother. 2025 Oct 14. 1-6
    Rilzabrutinib and Bruton tyrosine kinase inhibition for the treatment of persistent or chronic immune thrombocytopenia.
    Donald C Moore, P Christopher Parish, Justin R Arnall, Joseph B Elmes.
       INTRODUCTION: Immune thrombocytopenia (ITP) is an acquired autoimmune hematologic disorder characterized by autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and an increased risk of bleeding complications. Many patients will require additional treatment beyond first-line corticosteroids. In 2025, the US FDA approved rilzabrutinib, a Bruton tyrosine kinase inhibitor, for the treatment of adult patients with persistent or chronic ITP who have had an insufficient response to a previous treatment.
    AREAS COVERED: This review summarizes the pharmacology, efficacy, and safety of rilzabrutinib for the treatment of persistent or chronic ITP, followed by an expert opinion of the authors. PubMed was searched for relevant literature up to September 2025.
    EXPERT OPINION: The approval of rilzabrutinib represents an important advancement in the treatment of ITP and adds to the therapeutic armamentarium for this patient population. While rilzabrutinib has demonstrated efficacy compared to placebo in previously treated ITP patients, there is a lack of direct comparisons with other treatment options. The safety profile of rilzabrutinib differs from other BTK inhibitors approved for B-cell malignancies. Rilzabrutinib is subject to numerous drug-drug interactions, and careful selection of this agent and review of concomitant medications will be important to ensure its safe and effective use.
    Keywords:  Bruton tyrosine kinase inhibitor; Immune thrombocytopenia; hematology; rilzabrutinib
    DOI:  https://doi.org/10.1080/14656566.2025.2574850
  24. Blood Neoplasia. 2025 Nov;2(4): 100155
    Orally available decitabine prodrug OR-2100 induces mitotic perturbation for the treatment of double-hit lymphoma.
    Keisuke Kidoguchi, Hiroshi Ureshino, Yuta Yamamoto, Ryo Yanagiya, Yuki Kurahashi, Yuki Fukuda-Kurahasi, Yumeka Mine, Shigehisa Aoki, Kazutaka Nakashima, Hiroaki Miyoshi, Koichi Ohshima, Atsushi Kawaguchi, Shinya Kimura.
      Double-hit lymphoma (DHL), an aggressive B-cell lymphoma with a poor prognosis, harbors rearrangements of MYC and BCL2. The standard chemoimmunotherapy comprising R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) yields an unsatisfactory treatment response. Hypomethylating agents increase the susceptibility to malignant lymphoma via the restoration of tumor suppressor genes. Decitabine not only inhibits DNA methylation but also causes mitotic disruption, which leads to antileukemia effects through the covalent binding of DNA methyltransferase 1 to DNA. Previously, we developed an orally bioavailable prodrug of decitabine (OR-2100). Here, we investigated the efficacy and underlying mechanism of OR-2100 as a treatment for DHL. OR-2100 alone or in combination with key antilymphoma drugs, including doxorubicin and vincristine, suppressed the in vitro proliferation of DHL cell lines, particularly those with wild-type TP53. OR-2100 induced downregulation of CDCA8 and BIRC5 (baculoviral IAP [inhibitor of apoptosis] repeat-containing 5), the knockdown of which suppressed the proliferation of DHL cell lines. Both OR-2100 treatment and CDCA8 knockdown led to mitotic perturbation, suggesting that the disruption of mitosis may underlie the antitumor mechanism of OR-2100 given that the efficacy of OR-2100 was dependent on the TP53 status and that CDCA8 and BIRC5 are downstream targets of the E2F1 pathway. These findings suggest that the antitumor activity of OR-2100 may be mediated through inhibition of the E2F1 pathway. The combination of CHOP and OR-2100 reduced the tumor weight significantly in a xenograft mouse model without increased toxicities. The induction of mitotic perturbation might be a key antilymphoma mechanism for OR-2100, and the combination of OR-2100 and CHOP might be a promising treatment strategy for DHL.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100155
  25. Int J Radiat Oncol Biol Phys. 2025 Nov 15. pii: S0360-3016(25)06149-8. [Epub ahead of print]123(4): 947-954
    The Role of Radiation Therapy in the Management of Gray Zone Lymphoma.
    Omran Saifi, Scott C Lester, Nadia Laack, William G Rule, William G Breen, Allison Rosenthal, Stephen M Ansell, Thomas Habermann, Jose C Villasboas, Ernesto Ayala, Madiha Iqbal, Muhamad A Moustafa, Han Tun, Liuyan Jiang, Mohamed A Kharfan-Dabaja, Jennifer L Peterson, Bradford S Hoppe.
       PURPOSE: Gray zone lymphoma (GZL) is a rare disease that currently has poor treatment outcomes. The role of radiation therapy (RT) in the management of GZL is not well established. This trial is the largest study to report on the outcomes of patients with GZL treated with and without RT.
    METHODS AND MATERIALS: A retrospective review of 30 patients with GZL treated across 3 institutions from 2009 to 2021 was performed. Treatment response was assessed using end-of-treatment (EST) and/or interim (1) positron emission tomography (PET)-computed tomography or computed tomography scans, per Lugano criteria. A complete response (CR) on an interim PET scan (Deauville score, 1-3) was a rapid-early-response, whereas a partial response (PR) on an interim PET scan without progression was a slow-early-response (SER). For EST assessment, a Deauville score of 1 to 3 was considered CR, and a score of 4 to 5 without progression was considered PR. Event-free survival (EFS) was defined from initiation of frontline chemotherapy to disease progression/relapse, initiation of salvage therapy, or death.
    RESULTS: At a median follow-up of 4 years, the 2-year EFS was 26% for all patients, 33% for RT, and 23% for no-RT (P = .44). The 2-year EFS based on EST was 46% and 10% for CR and PR, respectively (P = .004). Patients with PR to chemotherapy who received RT had significantly better 2-year EFS compared with those who did not (17% vs 0%, P = .007). Among patients with SER, RT was also associated with improved 2-year EFS (33% vs 13%, P = .038). Patients with bulky mediastinal disease had a 2-year EFS of 43% with RT versus 11% without RT (P = .08).
    CONCLUSIONS: Patients with GZL have a high risk of relapse, and RT improves EFS, particularly for patients with SER, PR, and bulky mediastinal disease.
    DOI:  https://doi.org/10.1016/j.ijrobp.2025.08.012
  26. Blood. 2025 Oct 16. 146(16): 1874-1875
    BCMA: BeCoMing a new hope for AL amyloidosis.
    Efstathios Kastritis.
      
    DOI:  https://doi.org/10.1182/blood.2025030526
  27. Future Oncol. 2025 Oct;21(25): 3237-3244
    Plain language summary of IMerge, a Phase 3 study of imetelstat versus placebo in people with lower-risk myelodysplastic syndromes and anemia.
    Rami S Komrokji.
      
    DOI:  https://doi.org/10.1080/14796694.2025.2565877
  28. Blood Cancer Discov. 2025 Oct 17.
    ID2 suppresses multiple myeloma cell proliferation by repressing the activity of the transcription factor TCF3.
    Mariateresa Fulciniti, Yao Yao, Tommaso Perini, Jessica Fong Ng, Anaïs Schavgoulidze, Shuhui Deng, Jian Cui, Jessica Encinas Mayoral, Francesco Ladisa, Ryan M Young, Charles B Epstein, Cassandra M White, Christopher J Ott, Annamaria Gulla, Shannon M Matulis, Adam S Sperling, Eugenio Morelli, Lawrence H Boise, Moritz Binder, Raphael Szalat, Mehmet K Samur, Kenneth C Anderson, Nikhil C Munshi.
      Transcription factors and their cofactors are major and selective non-oncogene dependencies in multiple myeloma (MM) cells. By performing a gain-of-function perturbation screen in human MM cell lines, we identified the ID genes as putative suppressors of MM cell fitness. Among them, ID2 was found to be downregulated in MM patient cells and acted as a tumor suppressor by directly binding and repressing the basic helix loop helix factor TCF3, also known as E2A. Lower ID2 expression in MM cells conferred a proliferative advantage by increasing TCF3 activity, leading to a dependency on this transcription factor. In contrast, ID2 overexpression reduced TCF3 binding to DNA, which resulted in cell-cycle arrest and a halt in MM cell proliferation. The myeloma bone marrow milieu supported this process by further decreasing the expression of ID2 and enhancing TCF3 activity, partly via IL-6, revealing a mechanism by which the tumor microenvironment impacts MM cell behavior.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0048
  29. Indian J Hematol Blood Transfus. 2025 Oct;41(4): 947-950
    Impact of Dasatinib on Female Reproductive Health in Philadelphia-Positive Leukemia Patients.
    Shamita Kintada, Vanita Suri, Aashima Arora, Nalini Gupta, Tulika Singh, Naresh Sachdeva, Arihant Jain, Alka Khadwal, Pankaj Malhotra.
      Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), with patients now achieving life expectancy comparable to the general population. Despite the contraindication of TKIs during the first trimester of pregnancy, their effects on female reproductive health remain underexplored. This pilot case-control study evaluated the impact of Dasatinib on the female reproductive system in 25 women with CML or Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL), compared to 25 age-matched controls. Clinical histories, gynecological examinations, transvaginal ultrasonography, and serum Anti-Müllerian hormone (AMH) assessments were performed. There was no significant differences in menstrual cycle characteristics between patients and controls, although 12% of patients experienced shorter cycles and 8% reported heavier menstrual flow after initiating Dasatinib. Notably, patients on Dasatinib had significantly lower serum AMH levels (p < 0.005) and a higher incidence of low antral follicle count (AFC < 5 mm). Abnormal cervical cytology was observed in one patient, and two tested positive for HPV DNA. Dasatinib may subtly but significantly affect ovarian reserve and cervical health. Larger studies are needed to clarify these reproductive effects and inform clinical management in women receiving Dasatinib therapy.
    Keywords:  Acute lymphoblastic leukemia; CML; Menstrual disturbance; Ovarian functions; Pregnancy
    DOI:  https://doi.org/10.1007/s12288-024-01932-6
  30. J Exp Med. 2025 Dec 01. pii: e20250153. [Epub ahead of print]222(12):
    Heterozygous human JAK2V617F activates AhR to drive essential thrombocythemia and promote thrombosis.
    Li Zhou, Dongxiao Wu, Yabo Zhou, Dianheng Wang, Zhuo-Yu An, Peng Zhao, Shaoyang Lai, Zhenfeng Wang, Nannan Zhou, Jie Chen, Jiadi Lv, Xiaohui Zhang, Bo Huang.
      JAK2V617F causes >50% essential thrombocythemia (ET) and >90% polycythemia vera (PV). How such a single mutation causes distinct disorders remains a long-standing enigma. Here, we show that heterozygous JAK2V617F activates the transcription factor aryl hydrocarbon receptor (AhR), which biases MEP differentiation toward megakaryocytes in ET patients. In contrast, most PV patients' JAK2V617F exhibits a homozygous mutation that does not activate AhR. We found that JAK2V617F forms a heterodimer with JAK2 to recruit and activate STAT1, thereby inducing AhR activation and driving ET pathogenesis. However, JAK2 forms V617F homodimers in PV patients, which activate STAT5 and drive PV development. In addition to increasing platelet number, activated AhR may enhance platelet activity via the COX2-TXA2 axis. Importantly, targeting AhR inhibits thrombocytosis in JAK2V617F ET humanized mice. These findings not only elucidate the molecular mechanism of JAK2V617F ET but also provide a potential strategy for its treatment.
    DOI:  https://doi.org/10.1084/jem.20250153
  31. J Med Chem. 2025 Oct 13.
    Accelerated In Silico Discovery of SGR-1505: A Potent MALT1 Allosteric Inhibitor for the Treatment of Mature B-Cell Malignancies.
    Zhe Nie, Michael Trzoss, Andrew T Placzek, Lynnie Trzoss, Goran Krilov, Shulu Feng, Morgan Lawrenz, Min Ye, Netonia Marshall, Karen H Dingley, Robert D Pelletier, W George Lai, Jeffrey A Bell, Haifeng Tang, Paul Devine, Zhijian Liu, Peter Skrdla, Roman Shimanovich, Matt Liu, Renchao Wang, Xiaoming Xu, Robert Abel, Karen Akinsanya, Wu Yin.
      MALT1 is a key component of the CARD11-BCL10-MALT1 (CBM) complex downstream from BTK on the B-cell receptor signaling pathway. It is a key mediator of NF-κB signaling and considered a potential therapeutic target for several subtypes of non-Hodgkin's B-cell lymphomas. By applying advanced physics-based modeling techniques, including combining free energy calculations with machine learning methods and a chemistry-aware compound enumeration workflow, extensive sets of de novo design ideas were explored to quickly identify a novel hit series. Multiparameter optimization allowed efficient prioritization of molecules with good potency and drug-like properties during lead optimization, which led to the discovery of a highly potent MALT1 inhibitor, SGR-1505, with a well-balanced property profile. It demonstrated strong antitumor activity alone and in combination with BTK inhibitor in multiple in vivo B-cell lymphoma xenograft models and progressed to a phase 1 clinical trial in patients with mature B-cell neoplasms.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c01494
  32. Plants (Basel). 2025 Oct 05. pii: 3080. [Epub ahead of print]14(19):
    Turning Susceptibility into Strength: A New Era of Durable Resistance in Plants Through Genome Editing.
    Shallu Thakur, Simranjot Kaur, Sudeep Adhikari, Prerna Sabharwal, Yuqing Fu, Geoffrey Meru.
      In plants, resistance genes (R) are key players in combatting diseases caused by various phytopathogens. Typically, resistance relies on detecting a single pathogen-derived molecular pattern. However, R-gene-mediated resistance is often race specific, follows the gene-for-gene hypothesis, and can be overcome in field conditions as pathogens evolve. On the contrary, altering plant susceptibility genes (S-genes) facilitates compatibility and results in broad and durable resistance. S-genes are negative regulators present in plants and exploited by pathogens to facilitate their growth and cause infection. Several studies across crop species have reported manipulation of S-genes using genome editing to confer broad spectrum resistance. This review focuses on the plant defense mechanism against biotic stress, R-genes vs. S-genes, different types/classes of S-genes, different tools for S-gene discovery, and the use of gene editing technologies to target S-genes in addition to their applications, challenges, and future perspectives.
    Keywords:  CRISPR/Cas9; crops; disease resistance; genome editing; pathogens; susceptibility genes
    DOI:  https://doi.org/10.3390/plants14193080
  33. Leuk Lymphoma. 2025 Oct 15. 1-7
    Profound dFLC decrease after one cycle predicts superior outcome in patients with AL amyloidosis.
    Yang Liu, Jingyi Bi, Xuelin Dou, Nan Peng, Lei Wen, Liru Wang, Yanqiu Zhao, Yanqing Zhang, Yongqian Zhang, Yanping Cao, Wanjing Zhang, Jin Lu.
      The relationship between an early decrease in the difference between involved and uninvolved free light chains (dFLC) and clinical outcomes in AL amyloidosis is significant. We conducted a multicenter study (n = 86, baseline dFLC ≥ 50 mg/L) in which all patients received frontline daratumumab-bortezomib therapy. ROC analysis identified a dFLC reduction after one cycle (87% reduction, AUC = 0.82) as predictive of complete hematologic response (CHR). Patients achieving >87% dFLC or a very good partial response after one cycle were classified as optimal responders (O-HR), while those who did not were classified as suboptimal response (S-HR). The O-HR group had higher rate of CHR (90.5% vs. 43.5%, p < 0.001), cardiac response (68.9% vs. 36.8%, p = 0.017), and renal response (76.6% vs. 50.0%, p = 0.045) than the S-HR group. Profound dFLC decrease after one cycle suggests high CHR and organ response likelihood, supporting early treatment modification.
    Keywords:  AL amyloidosis; difference between the involved and uninvolved free light chain; early response
    DOI:  https://doi.org/10.1080/10428194.2025.2571200
  34. Haematologica. 2025 Oct 16.
    Defying age: myth or reality?
    Mary Eapen.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.289061
  35. Ann Hematol. 2025 Oct 14.
    Prognostic impact of GNRI-IPI score in octogenarians with diffuse large B-Cell lymphoma treated with R-CHOP.
    Eun-Jeong Jeong, Woochan Park, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Sang-A Kim, Koung Jin Suh, Ji-Won Kim, Se Hyun Kim, Jeong-Ok Lee, Jin Won Kim, Yu Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Jong Seok Lee, Soo-Mee Bang, Ji Yun Lee.
      Diffuse large B-cell lymphoma (DLBCL) outcomes decline in patients aged ≥ 80 years, with R-CHOP as standard therapy despite frequent dose reductions due to frailty. This study evaluates treatment outcomes and prognostic factors, including the Geriatric Nutritional Risk Index (GNRI), in this population. We retrospectively analyzed 102 patients aged ≥ 80 years with newly diagnosed DLBCL treated with full-dose or dose-attenuated R-CHOP at Seoul National University Bundang Hospital (2005-2024). Baseline characteristics, treatment delivery, toxicities, and survival were assessed using Kaplan-Meier methods and Cox proportional hazards models. Median age was 83 years; 57.8% had advanced-stage disease, and 55.8% were high/high-intermediate IPI risk. Median relative dose intensity was 54.0%; 65.7% completed treatment. Grade 3-4 toxicities occurred in 33.3%. At 2 years, overall survival (OS) was 71.8% and progression-free survival (PFS) was 67.2%. In multivariate analysis, low GNRI (< 81.6) independently predicted worse OS (HR 3.09, 95% CI 1.40-6.82, p = 0.005) and PFS (HR 2.84, 95% CI 1.34-6.02, p = 0.006); IPI ≥ 3 was associated with inferior PFS (HR 2.11, 95% CI 1.03-4.32, p = 0.042). The composite GNRI-IPI score stratified OS and PFS effectively, with high-risk showing worse survival (OS: HR 6.44, 95% CI 2.45-16.93, p < 0.001; PFS: HR 6.00, 95% CI 2.42-14.92, p < 0.001) and higher grade 3-4 toxicities (63.6% vs. 22.0% in low-risk, p = 0.023). GNRI-IPI enhances risk stratification and toxicity prediction in very elderly DLBCL patients, supporting nutritional integration in prognostication. Prospective validation is warranted.
    Keywords:  Diffuse large b-cell lymphoma; Elderly; Nutritional status; Prognostic factors; R-CHOP; Survival
    DOI:  https://doi.org/10.1007/s00277-025-06670-x
  36. Front Immunol. 2025 ;16 1647045
    Targeting PD-L1 for PCNS-DLBCL: from molecular effects to clinical translation.
    Jiajia Cao, Shuzhen Xiong, Shuni Zhang, Ningning Yue, Chongyang Wu.
      Primary central nervous system lymphoma (PCNSL) is a highly aggressive central nervous system lymphoma that has a high relapse rate and a 5-year survival rate of 30%-40% with conventional treatment. In about 95% of cases, Primary Central Nervous System Diffuse Large B-cell Lymphoma (PCNS-DLBCL) occurs. In some patients, the tumor microenvironment exhibited high levels of PD-L1, which may be linked to prognosis. The key mechanism for PD-L1 overexpression in EBV- tumor cells is the amplification of the 9p24.1 copy number, with signaling pathways such as JAK2 and NF-κB possibly playing a role in this process. Immune checkpoint inhibitors (anti-PD-1/PD-L1 mAb), particularly combined with BTK inhibitors, show promise in relapsed/refractory PCNSL. Still, there is no universally accepted therapeutic consensus. The blood-brain barrier limits drug penetration, and the spatiotemporal heterogeneity of PD-L1 remains a challenge. This paper discusses the expression of PD-L1 in PCNS-DLBCL and its relationship to prognosis, the efficacy of anti-PD-1 mAb and other drugs, and possible predictive markers of efficacy to provide a basis for anti-PD-1/PD-L1 mAb therapy, and the future of targeted PD-L1 therapy to achieve a high remission rate and individualized immunotherapy for PCNSL patients.
    Keywords:  PCNSL; PD-L1; biomarkers; immune checkpoint inhibitors; molecular targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1647045
  37. Cureus. 2025 Sep;17(9): e92366
    Zanubrutinib‑Induced Symmetrical Soft Tissue Forearm Swelling in a Patient With Waldenström Macroglobulinemia.
    Victor M Samperio, Aishwarya Ghonge, Constantin A Dasanu.
      Zanubrutinib is a second-generation Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of several indolent B-cell lymphomas. Although it has a more favorable safety profile than its predecessor, ibrutinib, rare adverse effects continue to emerge with broader clinical use. We report the case of an 87-year-old man with Waldenström macroglobulinemia (WM) who developed bilateral, non-pitting, soft tissue swelling of the forearms approximately 16 weeks after initiating zanubrutinib 160 mg orally twice daily. The swelling extended from the elbows to the hands, was symmetrical, non-tender, and not associated with any other symptoms. Doppler ultrasound ruled out deep vein thrombosis, and no alternative causes such as trauma, infection, or hypoalbuminemia were identified. A 50% dose reduction of zanubrutinib led to partial improvement, while complete resolution was observed 12 weeks after drug discontinuation. Unlike previously reported cases of BTK inhibitor-associated edema, which typically involve the lower extremities and present unilaterally or with associated skin changes, this case is unique in its bilateral presentation and upper extremity location without cutaneous involvement. The mechanism remains unclear but may involve vascular endothelial dysfunction or altered lymphatic drainage. Prompt recognition of this atypical presentation is essential for avoiding unnecessary interventions and optimizing therapeutic decisions.
    Keywords:  bruton tyrosine kinase (btk) inhibitor; musculoskeletal toxicity; soft tissue swelling; waldenström macroglobulinemia; zanubrutinib
    DOI:  https://doi.org/10.7759/cureus.92366
  38. Nutrients. 2025 Sep 28. pii: 3082. [Epub ahead of print]17(19):
    Pentadecanoic Acid (C15:0) at Naturally Occurring Circulating Concentrations Has Selective Anticancer Activities Including Targeting B-Cell Lymphomas with CCND3 Oncogenic Alterations.
    Stephanie Venn-Watson.
      Background/Objectives: While pentadecanoic acid (C15:0), present in whole dairy fat, has broad anticancer activities at high concentrations, the presence of C15:0 anticancer activities at naturally occurring circulating concentrations is less clear. Methods: Using an independent service to run the Eurofins OncoPanelTM Cell Proliferation Assay, C15:0 was screened for dose-dependent antiproliferation activities against 94 human cancer cell lines at 10 concentrations ranging between 1.5 nM and 50 µM. Oncogenic alterations were compared between cell lines in which C15:0 did or did not have antiproliferation activities. Results: C15:0 had dose-dependent antiproliferation activities (EC50 ≤ 50 µM) among 13 (13.8%) cancer cell lines, most of which were non-Hodgkin B-cell lymphomas (n = 8, 61.5% of C15:0-responsive cell lines), but also included liver (n = 2, 15.4%), breast (n = 2, 15.4%), and lung (n = 1, 7.7%) cancers. C15:0 had robust antiproliferation activities (EC50, IC50 and GI50 ≤ 50 µM) in four cell lines, all of which were non-Hodgkin B-cell lymphomas. When comparing oncogenic alterations among C15:0-responsive versus non-responsive cancer cell lines (n = 79 with available data on DepMap), 4 of 18 (22%) C15:0-responsive cell lines had a CCND3 mutation compared to 1 of 61 (1.6%) non-responsive cell lines (p = 0.007, OR = 17.1, 95% CI 1.8-165). Three of four (75%) of the most C15:0-responsive B-cell lymphomas had the CCND3 alteration (p = 0.0004, OR = 180, 95% CI 8.9-3632). Conclusions: C15:0 has selective dose-dependent anticancer activities at naturally occurring concentrations. The potential use of C15:0 against cancers with CCND3 genetic alterations warrants further exploration. Further, there is a need to better understand the potential role of nutritional C15:0 deficiencies and CCND3 alterations on the observed rise in certain types of cancers, especially among young adults.
    Keywords:  B-cell lymphoma; C15:0; CCND3; cancer; pentadecanoic acid
    DOI:  https://doi.org/10.3390/nu17193082
  39. Blood. 2025 Oct 17. pii: blood.2025029010. [Epub ahead of print]
    MRD intervention in AML: A new therapeutic horizon.
    Andrew H Wei, Harry J Iland, Courtney D DiNardo, John Reynolds.
      Acute myeloid leukemia (AML) is a polyclonal malignancy marked by high relapse rates despite initial morphologic remission. Although measurable residual disease (MRD) is an established prognostic tool, increasing evidence supports a role for pre-emptive, MRD-directed therapy. AML monitoring is hampered by absence of a universal MRD marker, necessitating a more personalized approach. NPM1 is suited to an MRD-directed strategy as the mutation is AML-defining and monitoring methods highly sensitive. Critically, rising NPM1mut levels portend clinical relapse with high fidelity and recent studies demonstrate that venetoclax-based regimens induce rapid and deep MRD responses in a high proportion of patients with NPM1mut MRD relapse. The range of MRD-directed treatment options are expanding and include FLT3 and menin inhibitors for MRD relapse driven by FLT3-ITD and KMT2A rearrangements, respectively. To overcome the logistical issue of multiple MRD markers and associated therapies, we have developed a multi-target, multi-arm platform trial named INTERCEPT. Novel features include the potential to adaptively expand the range of MRD markers and directed therapies, seamless transition of patients from a local to centralized MRD monitoring framework, a clinical decision rules approach to allocate treatment in a hierarchical and pre-specified manner, creation of parallel protocol appendices to enable multiple industry partners to co-exist with commercial independence, and development of approaches to minimize the "MRD relapse to treatment" time interval. The future success of MRD-directed therapy will depend on rapid diagnostic turnaround, coordinated logistics and innovative clinical trial designs able to keep pace with advances in MRD-detection technologies and associated targeted therapies.
    DOI:  https://doi.org/10.1182/blood.2025029010
  40. Int J Biol Sci. 2025 ;21(13): 5789-5801
    NR5A2 (located on chromosome 1q32) inhibits ferroptosis and promotes drug resistance by regulating phospholipid remodeling in multiple myeloma.
    Panpan Li, Jiadai Xu, Bei Xu, Xiaowen Hu, Yaqin Xiong, Yawen Wang, Peng Liu.
      Multiple myeloma (MM) is a prevalent hematologic malignancy with improved survival rates over recent decades, although still uncurable. MM with chromosome 1q Gain (1q+) are clinically and biologically heterogeneous. In this study, we found that NR5A2, located on chromosome 1q and encoding an essential transcriptional regulator of lipid metabolism, has higher mRNA expression in 1q+ patients and could further stratify the prognosis of MM patients. Omics data were analyzed and related experiments were conducted. We demonstrated for the first time that NR5A2 promotes the proliferation and invasion of MM cells by regulating phospholipid metabolism and further inhibit ferroptosis by reducing the related specific substrate in MM cells. Through integrated analysis of the lipid metabolism and proteome, MBOAT1 and MBOAT2 were determined to be the downstream targets of NR5A2. Furthermore, it has been determined that the high expression of NR5A2 is closely related to the resistance of MM cells to dexamethasone (Dexa). Interestingly, we found for the first time that arachidonic acid co-culture with MM cells can promote their sensitivity to Dexa and significantly reverse the resistance to Dexa caused by high expression of NR5A2. These findings provide insights into disease-causing mechanisms and new therapeutic targets for MM patients with 1q+.
    Keywords:  MBOAT1; MBOAT2; Multiple myeloma; NR5A2; ferroptosis; phospholipid remodeling
    DOI:  https://doi.org/10.7150/ijbs.113115
  41. Leuk Lymphoma. 2025 Oct 16. 1-8
    Pediatric-inspired regimen abrogates the poor prognosis of adult early T-cell precursor acute lymphoblastic leukemia.
    Jieping Lin, Chengming He, Zihong Cai, Junjie Chen, Jia Li, Changxin Yin, Huan Li, Chenhao Ding, Zhen Li, Zhixiang Wang, Xiaofang Li, Xuan Zhou, Bailin He, Wenhao Zhong, Li Xuan, Qifa Liu, Yang Xu, Hongsheng Zhou.
      Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is recognized as a high-risk subtype of T-cell acute lymphoblastic leukemia (T-ALL). While intensified chemotherapy has demonstrated potential benefits, there is a lack of comparative studies evaluating the effectiveness of adult versus pediatric treatment regimens for adult ETP-ALL. We compared the ETP-ALL patients (n = 65) treated with the pediatric-inspired regimen to the historical cohort treated with the adult regimen (n = 44). The results showed that the pediatric-inspired regimen significantly improved the complete remission rate (91% vs. 75%, p = .026). The five-year overall survival was markedly higher in the pediatric-inspired regimen cohort at 66.5% compared to 26.0% in the adult regimen cohort (p < .001). Event-free survival also improved significantly (63.4% vs. 18.5%, p < .001), with lower relapse rates (12.3% vs. 60.7%, p < .001). Multivariate analysis confirmed that ETP-ALL is not inferior to Non-ETP-ALL, suggesting that ETP-ALL should no longer be regarded as a high-risk factor in adult T-ALL.
    Keywords:  Pediatric-inspired regimen; T-cell acute lymphoblastic leukemia; early T cell precursor acute lymphoblastic leukemia
    DOI:  https://doi.org/10.1080/10428194.2025.2558921
  42. Leuk Lymphoma. 2025 Jul 26. 1-4
    Zanubrutinib is active for the treatment of relapsed primary vitreoretinal lymphoma.
    Amina Lateef Chaudhry, Patricia Chévez-Barrios, Paolo Strati.
      
    DOI:  https://doi.org/10.1080/10428194.2025.2539227
  43. Ann Hematol. 2025 Oct 15.
    Results from a US modified Delphi consensus to define disease progression and disease modification in polycythemia Vera.
    Prithviraj Bose, Emily Nagler, Muhammad Sarfraz Nawaz, Raajit K Rampal, Tsewang Tashi, Swapna Thota, John O Mascarenhas.
      Within 15 years of diagnosis, around 15% of polycythemia vera (PV) cases progress to post-PV myelofibrosis, and around 3% transform to acute myeloid leukemia within 10 years. Risk factors for disease progression include advanced age and the presence of certain acquired myeloid-relevant mutations. A better understanding of what defines disease progression in PV is essential when evaluating treatment options that enable disease modification and improved patient outcomes. A modified-Delphi method was used to convene a virtual steering group (SG) of seven US-based clinical physicians specializing in the management and treatment of PV. The group generated 41 consensus statements across six main domains. A survey was developed from these statements and shared with a broader panel of specialists, using a four-point Likert scale. The results were analyzed to determine the level of agreement for each statement. The consensus threshold was set at 75% agreement. A total of 61 responses were received from hematologist-oncologists (n = 56), oncologists (n = 3), and hematologists (n = 2). On analysis, 39/41 (95%) statements achieved consensus agreement, and 2/41 (5%) failed to achieve consensus. Consensus statements related to response assessment adjudication, treatment selection, and disease progression scored the highest, with 92% consensus among the wider panel. Based on the consensus, the SG agreed on a set of recommendations for defining disease progression and disease modification in PV. These recommendations aim to improve understanding of the disease course to support the development of more effective therapeutic strategies.
    Keywords:  Delphi consensus; Disease modification; Disease progression; Polycythemia vera; United states
    DOI:  https://doi.org/10.1007/s00277-025-06641-2
  44. J Med Case Rep. 2025 Oct 14. 19(1): 510
    Pulmonary toxicity induced by carfilzomib: a case report and review of the literature.
    Mateusz Ziarkiewicz, Aleksandra Zacny, Grzegorz Basak, Laretta Grabowska-Derlatka.
       BACKGROUND: Carfilzomib (Kyprolis™) is a second-generation proteasome inhibitor registered for the management of relapsed or refractory multiple myeloma. Drug safety profile includes hypertension, heart failure, and acute kidney failure. There are only scarce data on carfilzomib pulmonary toxicity.
    CASE DESCRIPTION: In this report, we present a case of a Caucasian man in his 50s diagnosed with multiple myeloma and treated with daratumumab-carfilzomib-dexamethasone as second-line therapy. After 5 months of treatment, the patient developed noninfectious interstitial pneumonitis with respiratory failure. After a thorough differential diagnosis, we identified the patient's symptoms as a direct result of drug administration. Carfilzomib withdrawal alone led to clinical and radiologic improvement, whereas reintroducing the therapy worsened the condition. Daratumumab as monotherapy was continued without adverse events. The precise cause of carfilzomib pulmonary toxicity remains unknown.
    CONCLUSION: Given the rarity of the reported syndrome, our case highlights the need to monitor pulmonary function on carfilzomib treatment, as well as the possibility of symptom cessation on early drug withdrawal without additional interventions.
    Keywords:  Carfilzomib; Interstitial pneumonitis; Multiple myeloma; Pulmonary toxicity
    DOI:  https://doi.org/10.1186/s13256-025-05564-w
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