bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–09–28
eighteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Losing CD38 in myeloma.
  2. Prognostic value of premaintenance FDG PET/CT response in patients with newly diagnosed myeloma from the CASSIOPEIA trial.
  3. Talquetamab plus daratumumab for the treatment of relapsed or refractory multiple myeloma in the TRIMM-2 study.
  4. Targeting Integrin α2 to Overcome Imatinib Resistance in Chronic Myeloid Leukemia Cells.
  5. Novel approaches to the use of hypomethylating agents in myeloid malignancies.
  6. G6b on the rise (or not?).
  7. Ziftomenib in Relapsed or Refractory NPM1-Mutated AML.
  8. Efficacy and toxicity of treatment of smoldering multiple myeloma: a systematic review and meta-analysis.
  9. Five-Year Outcomes of the POLARIX Study Comparing Pola-R-CHP and R-CHOP in Patients With Diffuse Large B-Cell Lymphoma.
  10. Silent TAM keeps quiet.
  11. High-risk genomic consensus validation for patients with newly diagnosed multiple myeloma using next-generation sequencing.
  12. Weighing the evidence: apixaban for pediatric leukemia.
  13. Detection of minimal residual disease in circulating cell-free DNA in acute myeloid leukemia.
  14. Different Colours of Polycythemia Vera: A Case Series.
  15. JAK Inhibitors for Treatment of VEXAS Syndrome: A Systematic Review of 186 Cases.
  16. Shelter in place: live CLL cells inside the bone marrow fibroblasts and its implication in residual disease persistence.
  17. Large B-cell lymphoma (LBCL): EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up.
  18. In pursuit of an HIV cure: from stem cell transplants to gene therapies.
  1. Blood. 2025 Sep 25. 146(13): 1529-1530
    Losing CD38 in myeloma.
    Maximilian Merz.
      
    DOI:  https://doi.org/10.1182/blood.2025029889
  2. Blood. 2025 Sep 24. pii: blood.2025030084. [Epub ahead of print]
    Prognostic value of premaintenance FDG PET/CT response in patients with newly diagnosed myeloma from the CASSIOPEIA trial.
    Françoise Kraeber-Bodere, Bastien Jamet, Sonja Zweegman, Aurore Perrot, Cyrille Hulin, Denis Caillot, Thierry Facon, Xavier Leleu, Karim Belhadj, Emmanuel Itti, Lionel Karlin, Clement Bailly, Mark-David Levin, Monique C Minnema, Caroline Bodet-Milin, Bart de Keizer, Jill Corre, Pieter Sonneveld, Philippe Moreau, Thomas Carlier, Cyrille Touzeau.
      The CASSIOPEIA trial (NCT02541383) demonstrated superior progression-free survival (PFS) with the addition of daratumumab to bortezomib, thalidomide, and dexamethasone (D-VTd) induction/consolidation and with daratumumab maintenance versus observation in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients. The companion study, CASSIOPET, assessed the prognostic value of pre-maintenance (PM) PET/CT response based on the standardized Deauville score on PFS and overall survival (OS) in addition to bone marrow (BM) minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) at 10-5 level. PM PET/CT was available for 225 patients: 112 patients treated with daratumumab after D-VTd (59) or VTd (53) and 113 patients followed by observation after D-VTd (56) or VTd (57). At PM, 92% of the 175 baseline PET-positive patients achieved PET-negativity, with a longer PFS in univariate analysis (HR, 0.48; P = 0.019) and a major trend of prolonged OS (HR, 0.37; P = 0.056). In univariate analysis, patients who achieved both PET and MFC negativity were found to have a better PFS (HR, 0.39; P<0.0001) than those who had at least one positive result. In daratumumab-treated patients, PM PET-negativity was associated with prolonged PFS and OS in univariate analysis (HR, 0.35; P = 0.0023 and HR, 0.32, P = 0.033, respectively) and double MFC and PET-negativity was independently associated with PFS by multivariate analysis (HR, 0.39, P = 0.0006). This study confirms the prognostic relevance of a PM PET response in NDMM patients treated with daratumumab in addition to MRD detection by MFC at the BM level.
    DOI:  https://doi.org/10.1182/blood.2025030084
  3. Blood. 2025 Sep 22. pii: blood.2025029360. [Epub ahead of print]
    Talquetamab plus daratumumab for the treatment of relapsed or refractory multiple myeloma in the TRIMM-2 study.
    Ajai Chari, Niels W C J van de Donk, Bhagirathbhai Dholaria, Katja C Weisel, Maria-Victoria Mateos, Hartmut Goldschmidt, Tom G Martin, Daniel Morillo, Donna Reece, Paula Rodriguez-Otero, Manisha Bhutani, Anita D'Souza, Albert Oriol, Laura Rosiñol, Nizar J Bahlis, Deeksha Vishwamitra, Sheri Skerget, Raluca I Verona, Kalpana K Bakshi, Lijuan Kang, Thomas J Prior, Lien Vandenberk, Jaszianne Tolbert, Sangmin Lee, Damiette Smit, Ralph Wäsch.
      Talquetamab, a GPRC5D-targeting bispecific antibody for relapsed/refractory multiple myeloma (RRMM), plus daratumumab may lead to deeper and more durable responses than either therapy alone. In the phase 1b TRIMM-2 study, patients with RRMM (at least 3 prior lines of therapy or double refractory to a proteasome inhibitor and an immunomodulatory drug) received subcutaneous talquetamab 0.4 mg/kg weekly (QW; "QW cohort") or 0.8 mg/kg every other week (Q2W; "Q2W cohort") plus daratumumab 1800 mg per the approved schedule. The primary end point was safety. Secondary end points included overall response and duration of response. Progression-free survival was an exploratory end point. Sixty-five patients (median 5 prior lines of therapy; 61.5% triple-class refractory; 24.6% bispecific antibody-exposed) received talquetamab plus daratumumab (QW, n = 14; Q2W, n = 51; median follow-up: 18.6 months). Most common adverse events were oral events, skin events, cytokine release syndrome, and infections. Grade 3/4 events occurred in 81.5%. Two patients had dose-limiting toxicities, both in the Q2W cohort (grade 3 stomatitis/oral mucositis and grade 3 maculopapular rash). Responses occurred in 71.4% (QW cohort) and 82.4% (Q2W cohort) of patients. Median progression-free survival was 23.3 and 21.2 months, respectively, in each cohort. Pharmacodynamic results suggest the immunomodulatory action of daratumumab contributes to a conducive environment for talquetamab by reducing immunosuppressive cells. Talquetamab plus daratumumab demonstrated promising efficacy outcomes in heavily pretreated patients, with a safety profile consistent with each agent as monotherapy. ClinicalTrials.gov ID: NCT04108195.
    DOI:  https://doi.org/10.1182/blood.2025029360
  4. Biomolecules. 2025 Aug 28. pii: 1245. [Epub ahead of print]15(9):
    Targeting Integrin α2 to Overcome Imatinib Resistance in Chronic Myeloid Leukemia Cells.
    Yalda Hekmatshoar, Tulin Ozkan, Arzu Zeynep Karabay, Sureyya Bozkurt, Aynur Karadag Gurel, Ozlem Kurnaz Gomleksiz, Tunc Fisgin, Asuman Sunguroglu.
      Chronic myeloid leukemia (CML) is a blood disorder caused by a genetic alteration that creates the BCR-ABL fusion gene, leading to continuous activation of cell growth signals and uncontrolled proliferation of the blood cells. Imatinib (IMA) resistance remains a major obstacle in CML treatment. Integrins, particularly integrin α2 (ITGA2), have been associated with cancer progression and drug resistance. In the current study, we investigated the role of ITGA2 in IMA resistance using IMA-sensitive K562 (K562S) and IMA-resistant K562 (K562R) cells. Our findings showed that ITGA2 is overexpressed in K562R cells and ITGA2 inhibitor E7820 (2.5 µM) treatment significantly decreased cell viability and induced apoptosis in both sensitive and resistant cells. Combination treatment with E7820 and imatinib enhanced pro-apoptotic gene expression (BAX, BIM) and decreased anti-apoptotic BCL2 levels in imatinib-resistant K562R cells. Flow cytometry confirmed ITGA2 inhibition at the protein level, and rhodamine assays revealed reduced MDR1 activity in treated cells. These results demonstrate that targeting ITGA2 may overcome imatinib resistance and offer a novel therapeutic strategy for CML.
    Keywords:  E7820; apoptosis; chronic myeloid leukemia; imatinib resistance; integrin α2
    DOI:  https://doi.org/10.3390/biom15091245
  5. Epigenomics. 2025 Sep 25. 1-12
    Novel approaches to the use of hypomethylating agents in myeloid malignancies.
    Justin Cheng, Casey O'Connell.
      Epigenetic dysregulation has been increasingly understood to be a key factor in the development of myeloid malignancies, often acting alongside genetic alterations to disrupt normal hematopoiesis. The inherent reversibility of epigenetic changes has provided an excellent opportunity for therapeutic intervention. Hypomethylating agents (HMA) preferentially alter gene expression in heavily methylated malignant myeloid cells by inhibiting DNA methyltransferases thereby altering gene expression. They have since become foundation therapies in myelodysplastic syndrome (MDS) and in older patients with acute myeloid leukemia (AML). However, complete responses to HMA monotherapy are limited and usually non-durable. In recent years, novel approaches have been sought to overcome resistance and expand the role of epigenetic therapies in MDS and AML as well as in less well-studied myeloid malignancies such as myeloproliferative neoplasms (MPNs) and MDS/MPN overlap syndromes. Combination regimens that synergistically pair HMAs or other epigenetically active therapeutics with agents targeting apoptosis, cellular metabolism, and immune evasion have also shown early promise in improving patient outcomes. Oral formulations of HMAs have made maintenance strategies more convenient and tolerable for patients, with demonstrated benefits in AML and ongoing investigations in MDS and post-transplant settings. This review will explore these novel therapeutic strategies in the treatment of myeloid malignancies.
    Keywords:  AML; Cancer epigenetics; HMAs; MDS; drug combinations; myeloid neoplasms
    DOI:  https://doi.org/10.1080/17501911.2025.2557179
  6. Blood. 2025 Sep 25. 146(13): 1531-1532
    G6b on the rise (or not?).
    Isabelle C Becker.
      
    DOI:  https://doi.org/10.1182/blood.2025029624
  7. J Clin Oncol. 2025 Sep 25. JCO2501694
    Ziftomenib in Relapsed or Refractory NPM1-Mutated AML.
    KOMET-001
       PURPOSE: Ziftomenib-a potent, highly selective, oral menin inhibitor-was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1-mutated (NPM1-m) and KMT2A-rearranged AML in the KOMET-001 phase I trial.
    METHODS: In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1-m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh).
    RESULTS: From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events.
    CONCLUSION: Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1-m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.
    DOI:  https://doi.org/10.1200/JCO-25-01694
  8. Ann Med. 2025 Dec;57(1): 2560679
    Efficacy and toxicity of treatment of smoldering multiple myeloma: a systematic review and meta-analysis.
    Lixin Quan, Qun Li, Chi Ma, Xinxin Cao, Chunyan Sun.
       OBJECTIVE: Smoldering multiple myeloma (SMM) is a slowly progressive, asymptomatic plasma cell disorder. This meta-analysis evaluated the efficacy and safety of novel agent-based therapies for SMM, particularly high-risk patients.
    METHODS: PubMed, Embase, Web of Science, Ovid MEDLINE, Scopus and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) and non-randomized studies from 2003 to 2024.
    RESULTS: Nineteen studies were included, comprising 5 RCTs and 14 non-randomized, single-arm trials. These studies involved a total of 1217 patients. Pooled analysis of intervention groups showed progression-free survival (PFS) and overall survival (OS) rate at 12 months of 94% (95% CI, 89%-98%) and 99% (95% CI, 97%-100%), respectively. The overall response rate (ORR) was 64% (95% CI, 50%-77%), and the complete response rate (CRR) was 12% (95% CI, 3%-25%). Minimal residual disease (MRD) negativity rate was 62% (95% CI, 42%-81%), and grade 3-4 adverse events (AEs) rate was 36% (95% CI, 30%-43%). As a comparison, we pooled data from the control groups of 5 RCTs, showing that PFS and OS rate-12m were 76% and 97%, respectively, with 0% CRR, 0% ORR and 25% grade 3-4 AEs. Subgroup analysis revealed high-risk SMM patients achieved higher PFS rate -12 m (97% vs. 91%), ORR (77% vs. 53%) and CRR (24% vs. 5%) compared to all SMM patients, with similar OS rate-12m (99% vs. 99%) and AEs rates (38% vs. 34%).
    CONCLUSION: Early intervention may delay progression and improve clinical responses, especially in high-risk SMM. However, adverse events (AEs) warrant caution. More well-designed RCTs are needed to confirm our findings.
    Keywords:  Smoldering multiple myeloma; early treatment; efficacy; meta-analysis; safety
    DOI:  https://doi.org/10.1080/07853890.2025.2560679
  9. J Clin Oncol. 2025 Sep 24. JCO2500925
    Five-Year Outcomes of the POLARIX Study Comparing Pola-R-CHP and R-CHOP in Patients With Diffuse Large B-Cell Lymphoma.
    Franck Morschhauser, Gilles Salles, Laurie H Sehn, Alex F Herrera, Jonathan W Friedberg, Marek Trněný, Georg Lenz, Jeff P Sharman, Charles Herbaux, John M Burke, Matthew Matasar, Graham P Collins, Neha Mehta-Shah, Lucie Oberic, Adrien Chauchet, Wojciech Jurczak, Yuqin Song, Antonio Pinto, Shinya Rai, Koji Izutsu, Richard Greil, Larysa Mykhalska, Juan M Bergua-Burgués, Matthew C Cheung, Ho-Jin Shin, Greg Hapgood, Eduardo Munhoz, Pau Abrisqueta, Jyh-Pyng Gau, Yanwen Jiang, Bruce McCall, Saibah Chohan, Matthew Sugidono, Mark Yan, Connie Lee Batlevi, Hervé Tilly, Christopher R Flowers.
      In the POLARIX study (ClinicalTrials.gov identifier: NCT03274492), polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) showed a significant progression-free survival (PFS) benefit versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated intermediate- or high-risk diffuse large B-cell lymphoma (DLBCL; median follow-up: 28 months). In this 5-year update, sustained PFS benefits favoring Pola-R-CHP were observed. In the global intention-to-treat population (N = 879; median follow-up: 64.1 months), Pola-R-CHP demonstrated a significant PFS benefit over R-CHOP (hazard ratio [HR], 0.77 [95% CI, 0.62 to 0.97]), with 5-year PFS rates of 64.9% (95% CI, 59.8 to 70.0) and 59.1% (95% CI, 53.9 to 64.3), respectively. Although not statistically significant, overall survival analysis showed a HR of 0.85 (95% CI, 0.63 to 1.15) at the 5-year data cut compared with 0.94 (95% CI, 0.67 to 1.33) at the 2-year data cut. In the expanded population, 46 and 62 patients had lymphoma-related deaths in the Pola-R-CHP and R-CHOP arms, respectively. Exploratory analyses showed favorable 5-year survival rates with Pola-R-CHP in high-risk subgroups, including activated B-cell DLBCL and International Prognostic Index score 3-5. Long-term tolerability was similar between treatment arms. Findings confirm Pola-R-CHP represents a standard of care for frontline treatment of DLBCL.
    DOI:  https://doi.org/10.1200/JCO-25-00925
  10. Blood. 2025 Sep 25. 146(13): 1528-1529
    Silent TAM keeps quiet.
    Jeffrey A Magee.
      
    DOI:  https://doi.org/10.1182/blood.2025030018
  11. Blood. 2025 Sep 24. pii: blood.2025029999. [Epub ahead of print]
    High-risk genomic consensus validation for patients with newly diagnosed multiple myeloma using next-generation sequencing.
    Anaïs Schavgoulidze, Aurore Perrot, Xavier Leleu, Titouan Cazaubiel, Marie-Lorraine Chretien, Pierre Feugier, Karim Belhadj, Salomon Manier, Murielle Roussel, Sabine Brechignac, Frederique Orsini Piocelle, Mohamad Mohty, Jean Marc Schiano de Colella, Margaret Macro, Didier Adiko, Mamoun Dib, Jean Fontan, Carine Motard, Didier Bouscary, Laurent Pascal, Virginie Roland, Francois Lifermann, Jana Armelle Bakala, Lydia Montes, Celine Kennel, Philippe Rey, Valentine Richez, Faiza Keddar, Laurent Frenzel, Claire Calmettes, Carine Chaleteix, Isabelle Plantier, Emilie Chalayer, Anna Schmitt, Christophe Roul, Hélène Demarquette, Chloe Cerutti, Luka Pavageau, Laure Derrier, Hervé Avet-Loiseau, Jill Corre.
      The prognostic heterogeneity of multiple myeloma is mainly driven by genomic features of myeloma cells. The International Myeloma Society (IMS) / International Myeloma Working Group (IMWG) recently proposed a high-risk (HR) genomic model in order to have a consensus definition of genomic risk. We performed NGS panel in 6528 new diagnosed myeloma patients (NDMM) and 1583 patients at first relapse, between 2019 and 2024. We observed that 22.4% of patients at diagnosis and 36.7% at first relapse were HR according to the Consensus Genomic Staging (CGS). Clinical data were available for 2695 patients at diagnosis. After a median follow-up of 35 months, the median PFS was 30 months for HR NDMM patients, vs 51 months for standard-risk (SR) (p<0.0001). HR cytogenetic criteria from the Revised-ISS score were not able to discriminate patients in HR nor SR IMS/IMWG genomic subgroups. Looking at each criteria independently, we found that the presence of del(17p), TP53 mutation, biallelic del(1p32), or the combination of intermediate risk cytogenetics (gain 1q, del(1p32), t(4;14), t(14;16), t(14;20)) significantly reduces the PFS compared with standard-risk patients. Moreover, patients cumulating several criteria had an even worse prognosis. Among SR patients according to the genomic definition with normal creatinine, median PFS of those with high beta2-microglobulin was not significantly different from patients with normal beta2-microglobulin level. This study validates the IMS/IMWG genomic definition of high-risk myeloma in a large cohort of patients diagnosed from 2019.
    DOI:  https://doi.org/10.1182/blood.2025029999
  12. Blood Adv. 2025 Sep 23. 9(18): 4748-4749
    Weighing the evidence: apixaban for pediatric leukemia.
    Leslie Raffini, Hilary Whitworth.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025016948
  13. Sci Rep. 2025 Sep 23. 15(1): 32679
    Detection of minimal residual disease in circulating cell-free DNA in acute myeloid leukemia.
    Charlotte Sommer, Hildegard I D Mack, Madeleine C Killer, Petra Ross, Andrea Nist, Thorsten Stiewe, Andreas Neubauer, Cornelia Brendel, Elisabeth K M Mack.
      Minimal/measurable residual disease (MRD) in Acute Myeloid Leukemia (AML) is defined as persistent leukemic cells below cytomorphological detection threshold. Next generation sequencing (NGS) of circulating cell-free DNA (cfDNA) to profile cancer-associated mutations has been shown to allow for quantification of disease burden in solid tumors and has also been suggested to enable minimally invasive follow-up of AML patients. In this pilot study we investigated the technical sensitivity and potential prognostic implications of cfDNA-based MRD monitoring in AML after allogeneic stem cell transplantation in comparison to donor chimerism analysis or, respectively, after consolidation chemotherapy. 75 cfDNA samples from 29 patients were analyzed by targeted NGS using a commercially available 10- or 37-gene hotspot panel (VariantPlex Core AML or Core Myeloid panel, ArcherDx). Patients' leukemias exhibited 1-7 mutations as determined by routine diagnostics. Only previously identified mutations were considered for MRD evaluation. cfDNA was isolated in sufficient amounts for NGS from all samples (total yield 24 ng-5.2 µg). The sensitivity of variant detection increased with higher overall read count and higher mutation-specific coverage (variant allele frequency [VAF] range 0.08-100%). At least one previously known mutation was identified in 32/55 samples (58%, VAF 0.08-78.04%) which were taken during hematological complete remission (CR) in both patients after allogeneic stem cell transplantation (aHSCT) and patients after consolidation chemotherapy. In patients after aHSCT (n = 25), at least one previously known mutation was detected in 16/29 cfDNA samples (55.1%, VAF 0.08-6.7%) obtained when donor chimerism was ≥ 90% and in 6/6 samples (100%, VAF: 0.88-63.77%) with reduced donor chimerism. Probability of progression-free survival 17 months after aHSCT in patients with donor chimerism ≥ 90% but mutation-positive cfDNA was 64% compared to 100% in patients with undetectable MRD. In patients after consolidation chemotherapy, cfDNA was positive in all samples taken during CR (n = 4; VAF 0.26-29.84%) and non-CR (n = 4; VAF 8.46-100%). Our results indicate that NGS of cfDNA is suitable for MRD monitoring in AML and offers higher sensitivity for detecting residual leukemic cells than chimerism analysis in patients after aHSCT. Further studies are needed to evaluate clinical relevance of MRD status as determined in cfDNA.
    Keywords:  Acute myeloid leukemia; Cell-free DNA; Minimal residual disease; Next-generation sequencing
    DOI:  https://doi.org/10.1038/s41598-025-20589-3
  14. Cureus. 2025 Aug;17(8): e90913
    Different Colours of Polycythemia Vera: A Case Series.
    Naveenkumar Viswanathan, Sahasyaa Adalarasan, Sandhiya T, Yogesh S.
      Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by increased red blood cell mass, often with leukocytosis and thrombocytosis, predisposing to thrombotic and hemorrhagic events. We report three cases with varied presentations: a 38-year-old man with headaches, dizziness, blurred vision, and fatigue; a 54-year-old woman with acute myocardial infarction; and a 60-year-old man with acute ischemic stroke. All had elevated hemoglobin/hematocrit, low erythropoietin, and positive JAK2 mutation. Management with phlebotomy, hydroxyurea, and supportive measures led to good recovery. These cases illustrate the spectrum of PV manifestations, emphasizing early diagnosis and treatment to reduce morbidity and mortality.
    Keywords:  different presentation; jak2 mutation; myeloproliferative; polycythemia; polycythemia vera (pv)
    DOI:  https://doi.org/10.7759/cureus.90913
  15. Dermatol Res Pract. 2025 ;2025 9127126
    JAK Inhibitors for Treatment of VEXAS Syndrome: A Systematic Review of 186 Cases.
    Saeed Bahramian, Patrick Fazeli, Arezou Rafati, Sardar Demokri, Huria Memari, Amirali Soheili, Farzad Esmaeili, Mohammad Pourmehdi Ardebili, Haniye Erfani, Seyed Mohammad Vahabi.
      Objectives: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an autoinflammatory disease with a wide spectrum of manifestations and no standard treatment. Janus kinase inhibitors (JAK-I) are small-molecule drugs that affect many molecular pathways. We aim to investigate the safety and efficacy of JAK-I in the treatment of VEXAS syndrome. Methods: A systematic search was conducted using MeSH terms/keywords related to JAK-I and VEXAS syndrome through PubMed/Medline, Scopus, Web of Science, and Embase until July 6, 2025. Results: We included 29 articles: 8 cohort, 8 case series, and 13 case reports. Our study includes data for 186 cases. The mean age was 69.64 years, and 83.33% were male. The most frequent manifestations were skin lesions (64.51%), fever (64.51%), arthritis and arthralgia (61.29%), lung involvement (31.72%), and venous thrombosis (24.19%). In general, 33.87% had a complete response, and 29.57% had a partial response. Ruxolitinib was used in 117 patients. Thirty-four out of 117 (29.06%) experienced complete to partial remission. Tofacitinib was used in 31 patients. About 29% of them showed complete to partial remission. Baricitinib was used in 25 patients; 12% had complete remission, and 16% had partial remission. Upadacitinib was used in 13 patients, which led to a complete remission in 38.46%. Filgotinib was used in four patients, leading to partial remission in one case. Among all, 36.55% showed adverse effects. Of these, eight were on Ruxolitinib, two on Tofacitinib, two on Baricitinib, and three on Upadacitinib. Conclusion: JAK-I seems to be a promising treatment option with tolerable adverse effects for VEXAS syndrome.
    Keywords:  JAK inhibitors; Janus kinase; UBA1 mutation; VEXAS syndrome
    DOI:  https://doi.org/10.1155/drp/9127126
  16. Blood Neoplasia. 2025 Nov;2(4): 100142
    Shelter in place: live CLL cells inside the bone marrow fibroblasts and its implication in residual disease persistence.
    Pin Lu, Carrie A Franzen, Aldana Vistarop, Andrey Efimov, Sk Abrar Shahriyar, Shengchun Wang, Shilpa Rao, Marcus Messmer, Shazia Nakhoda, Edna Cukierman, Shuo Ma, Janusz Franco-Barraza, Juehua Gao, Y Lynn Wang.
      Bruton tyrosine kinase inhibitors (BTKis) have been successful in treating B-cell malignancies including chronic lymphocytic leukemia (CLL). However, a deep response to BTK inhibition is uncommon. It is unknown what mechanism results in minimal residual disease (MRD) persistence. Cell-in-cell (CIC) describes the microscopic observations of embodiment of an intact cell by another whole cell. CIC has been sporadically described by pathologists in human fixed tissues for over a century. However, its biological, pathological, and clinical significance remains obscure. In this study, we investigated human primary CLL samples using a clinically faithful ex vivo model system that accurately recapitulates the lymphoma tumor microenvironment. We observed that CLL cells were actively internalized by Bone marrow fibroblasts (BMF) and remained alive and mobile for days. We hypothesized that live CIC may represent a new mechanism for tumor cells to evade therapies and survive as residual disease. Indeed, CIC events were identified directly in the bone marrow of patients being treated with BTKis. Using confocal microscopy, we demonstrated that the ex vivo exposure to BTKi drove CLL cells into BMF. We further showed that CIC inside the BMF were indeed protected from drug-induced apoptosis compared to cells that stayed outside. Mechanistically, we identified that CXCR4 receptor was required for CIC because CXCR4 antagonists and CRISPR-mediated genetic depletion completely abrogated CIC. Altogether, human direct evidence and ex vivo data implicate CIC in disease persistence. Targeting tumor-stroma interaction via CXCR4 inhibition could constitute a new therapeutic approach to minimize MRD and future relapses.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100142
  17. Hemasphere. 2025 Sep;9(9): e70207
    Large B-cell lymphoma (LBCL): EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up.
    Catherine Thieblemont, Maria Gomes Da Silva, Sirpa Leppä, Georg Lenz, Anne-Ségolène Cottereau, Christopher Fox, Armando Lopez-Guillermo, Timothy Illidge, Wojciech Jurczak, Hans Eich, Igor Aurer, Marek Trneny, Andy Andreas Rosenwald, Andrew Davies, Ben Gerben Zwezerijnen, Natacha Bolanos, Maja Marković, Jean-Philippe Jais, Florence Broussais, Martin Dreyling, Umberto Vitolo, Hervé Tilly, Marie-José Kersten.
      Large B-cell lymphoma (LBCL) accounts for about one-third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B-cell lineage and identifying variants. MYC and BCL2 rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET-CT). The International Prognostic Index (IPI) aids risk stratification. PET-CT is critical for assessing treatment response and guiding strategies. First-line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for advanced stages depending on IPI scores. Primary mediastinal B-cell lymphoma (PMBCL) management favors R-CHOP given every 14 days (R-CHOP14) or dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or <80 with poor fitness), need geriatric assessment to guide therapy, often R-miniCHOP or non-anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS-IPI scores and specific anatomical sites help identify high-risk patients; magnetic resonance imaging (MRI) and colony-stimulating factor (CSF) analysis are recommended. Approximately 30%-40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (<1 year or ≥1 year). For those refractory or relapsing within <1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART-naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow-up includes clinical examination for 2 years and management for long-term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress.
    DOI:  https://doi.org/10.1002/hem3.70207
  18. Front Genome Ed. 2025 ;7 1634193
    In pursuit of an HIV cure: from stem cell transplants to gene therapies.
    Jennifer Clees, Maya Basic, Pedro E Cruz, Servio H Ramirez, Allison M Andrews.
      Since 2009, seven people living with human immunodeficiency virus (PLHIV) have been declared cured of HIV after receiving allogeneic hematopoietic stem cell transplants (alloHSCTs) to treat hematologic malignancies. In this sense, cure signifies the absence of viral DNA/RNA and undetectable viral loads without the use of antiretroviral therapy (ART). Five of these transplants utilized mutated C-C motif chemokine receptor type 5 (CCR5Δ32/Δ32) stem cells. Much has been learned from these and past cases, and although effective, bone marrow transplants cannot be easily or safely translated to cure the millions of PLHIV across the globe. A successful eradicating cure includes both the prevention of HIV from entering new cells and the elimination of tissue reservoirs. Protecting hematopoietic stem and progenitor cells (HSPCs) from infection is a key consideration since there is evidence that HSPCs themselves, not only their descendants, are susceptible to infection. Gene therapy approaches have the potential to bring about an eradicating HIV cure that could be highly effective, broadly applicable, less expensive, and practical to implement. Current strategies are tackling this problem by removing the integrated proviral DNA from infected cells and/or eliminating the co-receptor(s) necessary for HIV viral entry into target cells. Both approaches hold promise, but they require overcoming key challenges (i.e., vector toxicity, transduction efficacy, elimination of reservoir cells, etc.). This review summarizes and examines the lessons learned about curing HIV through bone marrow transplants, the current gene therapy methodologies, pitfalls of eradication strategies as well as future directions of the field.
    Keywords:  HIV; bone marrow; cure; gene therapy; hematopoietic stem cells
    DOI:  https://doi.org/10.3389/fgeed.2025.1634193
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