bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–08–31
thirty papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό



  1. Blood Adv. 2025 Aug 22. pii: bloodadvances.2024014975. [Epub ahead of print]
      Relapsed/refractory (R/R) follicular lymphoma (FL) is a chronic disease often requiring multiple lines of therapy. Covalent (c) Bruton tyrosine kinase inhibitor (BTKi) monotherapy has resulted in variable response rates, yet patients invariably experience relapse. While newer therapies such as bispecific antibodies and CAR T cell therapy are available, patient access and eligibility remain challenging. Here, we report the safety and efficacy of pirtobrutinib, a non-covalent (reversible) BTKi, monotherapy in a R/R FL patient cohort from the multicenter phase 1/2 BRUIN study. Key endpoints included investigator-assessed ORR per Lugano 2014 criteria, DoR, PFS, OS, and safety. Among 48 patients with FL, the median age was 64.5 years (range, 37.0-85.0). Patients had received a median of 3 (range, 1-12) prior lines of therapy. The ORR with pirtobrutinib was 50.0% (95% CI, 35.2-64.8), and median DOR was 5.5 months (95% CI, 3.7- NE). Median PFS was 5.8 months (95% CI, 3.8-8.1), and median OS was NE, with a median follow-up of 20.4 months (IQR, 13.7, 27.5). The estimated DOR, PFS, and OS rates at 18 months were 41.0% (95% CI, 20.1-60.9), 32.3% (95% CI, 19.1-46.2), and 78.3% (95% CI, 62.1-88.1), respectively. Pirtobrutinib was well-tolerated with two patients (4.2%) discontinuing treatment due to AEs (one treatment-related) and four patients (8.3%) having dose reductions due to AEs (all treatment-related). Pirtobrutinib showed promising efficacy and was well tolerated in this cohort of heavily pre-treated patients with R/R FL warranting further investigation.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014975
  2. Clin Cancer Res. 2025 Aug 25.
       PURPOSE: Lenalidomide maintenance is the most frequently utilized approach for newly diagnosed multiple myeloma (MM) patients following induction therapy with/without consolidative high-dose melphalan and autologous stem cell transplantation. Baseline and longitudinal measurable residual disease (MRD) negative status is a well-established positive predictive sign in lenalidomide maintenance patients. However, the clinical utility of serial MRD assessments remains uncertain, as there is no consensus on the clinical management of MRD-resurgence (MRDres) or stable remissions in patients positive for MRD.
    EXPERIMENTAL DESIGN: Here we report the complete and final results of a phase 2, single-arm study of 5 years of continuous lenalidomide maintenance in MM patients following unrestricted upfront therapy, along with exploratory peripheral blood T cell profiling experiments performed via high-dimensional spectral cytometry.
    RESULTS: Patients with MRDres had inferior PFS to those with sustained MRD-negativity at the 1- and 2-year landmarks (P=0.036, P=0.0014 respectively); however, myeloma progression only occurred within 2 years of MRDres in 36% of patients, with no progression observed in the remaining 64% of patients at last follow-up. Exploratory peripheral blood T cell profiling experiments throughout the trial period identified an immune signature of early relapse in patient cohorts both negative and positive for MRD at the start of maintenance therapy. T cell profiles enriched with activated cytotoxic effectors predicted early relapse while quiescent T cell profiles enriched with naïve T cell populations predicted durable remissions.
    CONCLUSIONS: This "immune-MRD" status showed predictive potential, and segregated patients with MRDres and early disease progression from patients with sustained remission despite MRDres.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-0572
  3. Int J Hematol. 2025 Aug 27.
    Japan Adult Leukemia Study Group
      This study compared dasatinib and imatinib in adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). Using pooled data from three JALSG prospective trials (Ph + ALL202, Ph + ALL208, Ph + ALL213), we analyzed outcomes for 206 patients aged 15-64 years treated with dasatinib (n = 74) or imatinib (n = 132) in combination with chemotherapy. We applied propensity score matching (1:1) and inverse probability of treatment weighting to minimize selection bias and balance baseline characteristics. Dasatinib plus chemotherapy was associated with significantly higher complete molecular response rates after induction therapy compared with imatinib. In the propensity score-matched cohort (n = 68 patients per group), 3-year event-free survival (EFS) was significantly higher with dasatinib (73 vs. 49%, P = 0.01), as was 3-year overall survival (OS) (85 vs. 60%, P = 0.004). Multivariate analysis, incorporating allogeneic stem cell transplantation in first complete remission as a covariate, confirmed that dasatinib had an independent favorable prognostic impact on EFS (hazard ratio [HR], 0.54; P = 0.02) and OS (HR, 0.39; P = 0.003). Although the 3-year cumulative incidence of relapse tended to be lower with dasatinib (18 vs. 40%, P = 0.07), non-relapse mortality was comparable between groups (8.8 vs. 12%, P = 0.33). This analysis demonstrates improved survival with dasatinib-based therapy in adult Ph + ALL, informing tyrosine kinase inhibitor selection in treatment planning.
    Keywords:  Dasatinib; Imatinib; Philadelphia chromosome-positive acute lymphoblastic leukemia; Tyrosine kinase inhibitor selection
    DOI:  https://doi.org/10.1007/s12185-025-04058-1
  4. Blood. 2025 Aug 27. pii: blood.2025029215. [Epub ahead of print]
      Bispecific T cell engagers (TCE) targeting BCMA and CD3 induce deep hematologic responses in approximately 60% of heavily pre-treated multiple myeloma (MM) patients. We and others found that high tumor burden leads to resistance to TCE and novel strategies are urgently needed to improve responses in this setting. Ikaros-degraders, including IMiDs and CELMoDs, represent logical partners for TCE due to their direct anti-MM effects and additional immune stimulatory activity; however, it is unclear how to optimally combine them with TCE. Taking advantage of the immunocompetent IMiD-sensitive Vk*MYChCRBN murine model of MM, we optimized strategies to overcome primary resistance to BCMA-TCE and achieve sustained remission, while maintaining a manageable safety profile. The addition of anti-PD1 and pomalidomide reduced the T cell exhaustion that occurs in response to TCE in high tumor burden settings. This allowed for a higher degree of T cell activation and significant improvement in response rates but also increased risk of lethal cytokine release syndrome (CRS). To moderate the response and prevent CRS, we evaluated Ikaros-degraders and dexamethasone with step-up dosed TCE. Pre-treatment with iberdomide and dexamethasone reshaped the bone marrow T cell compartment, promoted infiltration of naïve T cells, and generated 100% response rates and the longest survival in subjects with high tumor burden. This was accompanied by more favorable T cell profiling, with limited expansion of regulatory T cells and exhaustion. In total, administering TCE following dexamethasone and iberdomide treatments provided deeper and more durable responses with reduced risk of CRS.
    DOI:  https://doi.org/10.1182/blood.2025029215
  5. Blood Adv. 2025 Aug 22. pii: bloodadvances.2025016801. [Epub ahead of print]
      Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma (NHL). Despite multiple approved Bruton tyrosine kinase inhibitors (BTKi), resistance to BTKi continues to pose a major clinical challenge. The transcription factor SOX11 is expressed in most MCL patients and is associated with poor outcomes. We have previously demonstrated SOX11-dependent BCR signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling by transcriptional activation of the PAX5-CD19 axis. The translational potential of these results is significant as scRNA-seq data show SOX11 is overexpressed in Ibrutinib-resistant patients as compared to Ibrutinib-sensitive patients. Treatment with the SOX11 DNA-binding inhibitor (SOX11i) significantly reduces the expression of PAX5, CD19, and components of BCR signaling in both Ibrutinib-sensitive and Ibrutinib-resistant cell lines. Importantly, SOX11i was able to demonstrate cytotoxicity in cells derived from Ibrutinib-resistant, Venetoclax (BCL2i) and CAR-T resistant PDX models in vitro. SOX11i treatment reduced the tumor growth in vivo in a MCL xenograft model without any significant toxicity. SOX11 inhibition offers significant potential for MCL patients, especially BTKi resistant patients, by targeting upstream resistance mechanisms.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016801
  6. Front Oncol. 2025 ;15 1644661
      Myelofibrosis (MF) is a philadelphia chromosome-negative chronic myeloprolifera- tive neoplasm.It has a worse prognosis than polycythemia vera and essential thrombocy- themia.At present,both Chinese and foreign guidelines recommend ruxolitinib as first-line treatment for IPSS/DIPSS/DIPSS-Plus patients with splenomegaly in intermediate-risk-2 and high-risk MF-CP.However,long-term follow-up revealed possible increase in the discontinuation rate of ruxolitinib due to drug resistance and other reasons with the prolongation of the treatment duration. At this study,it imposes a great challenge for clinical management owing to the lack of standard treatment for patients who have lost efficacy due to drug resistance,and the absence of subsequent treatment strategies. Significantly, venetoclax combined with azacytidine, with or without the use of ruxolitinib, was reported to be effective and safe for patients in MF-accelerated/acute phase.Here, we report a case of MF-CP patient who was unresponsive to ruxolitinib, with therapeutic response after applying venetoclax and azacytidine in combination with ruxolitinib. After treatment, the patient showed improved condition. After two courses of treatment with venetoclax and azacytidine combined with ruxolitinib, the patient has been continuously treated with oral ruxolitinib and has achieved a therapeutic effect for more than 1 year. The treatment response of this patient we reported provides a new safe and effective treatment method for MF-CP patients who are no longer responsive to ruxolitinib.
    Keywords:  azacytidine; drug-resistant; myelofibrosis; ruxolitinib; treatment; venetoclax
    DOI:  https://doi.org/10.3389/fonc.2025.1644661
  7. NEJM Evid. 2025 Sep;4(9): EVIDoa2500017
       BACKGROUND: Myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 rearrangements (MLN-FGFR1) are associated with poor prognosis. They are caused by chromosome 8p11 rearrangements that result in FGFR1 fusion genes and constitutive FGFR1 activation. We report on a phase 2 study, in which there were no concurrent control patients, termed FIGHT-203, in which we evaluated the FGFR1-3 inhibitor, pemigatinib, for the treatment of MLN-FGFR1.
    METHODS: We assigned eligible patients to receive oral pemigatinib 13.5 mg once daily (2 weeks on followed by 1 week off or continuously). End points included complete response rate (primary) and complete cytogenetic response rate. Responses were assessed locally by investigators per protocol-defined criteria and were retrospectively adjudicated by a central review committee using criteria defined by the committee.
    RESULTS: Of 47 treated patients (safety population), 45 had confirmed FGFR1 rearrangement and were analyzed for efficacy; of these patients, 24 (53%) were in the chronic phase of illness; 18 (40%) were in blast phase; and three previously treated patients (7%) exhibited the rearrangement without morphologic bone marrow or extramedullary involvement. The overall complete response rate, as determined by central review, was 74% (31 out of 42); this occurred in 96% (23 out of 24) of patients in chronic phase and 44% (8 out of 18) of patients in blast phase. A complete cytogenetic response was observed in 73% (33 out of 45) of patients overall, consisting of 88% (21 out of 24) of patients in chronic phase, 50% (9 out of 18) of patients in blast phase, and all three patients who had a rearrangement only. The median duration of complete response was not reached (95% confidence interval, 27.9 months to not reached). The most common any-grade treatment-emergent adverse event was hyperphosphatemia (76%); the most common grade-3-and-over event was stomatitis (19%). Pemigatinib discontinuation, interruption, and dose reduction occurred in 5 (11%), 30 (64%), and 28 (60%) patients, respectively.
    CONCLUSIONS: In our study, pemigatinib manifested near complete efficacy in chronic-phase patients with MLN-FGFR1, while the complete response rate was close to 50% in blast-phase patients. Toxicities were manageable with dose modifications. (Funded by Incyte Corporation; FIGHT-203 ClinicalTrials.gov number, NCT03011372.).
    DOI:  https://doi.org/10.1056/EVIDoa2500017
  8. Mol Cancer Ther. 2025 Aug 20.
      TUB-010 is a next-generation antibody-drug conjugate (ADC) targeting CD30 expressed on various hematopoietic malignancies such as Hodgkin lymphoma. Among the therapeutic options for patients with relapsed and refractory CD30-positive cancers is brentuximab vedotin (Adcetris), an MMAE-delivering anti-CD30 ADC with a mean drug-to antibody ratio (DAR) of 4. Adcetris exhibits a high response rate at the cost of significant toxicities, likely driven by the payload MMAE and instability of the maleimide conjugation chemistry. TUB-010 uses the same antibody and payload as Adcetris, but is based on the Tub-tag conjugation strategy, which stably attaches MMAE to the hydrophilic Tub-tag peptides on the light chains via chemoenzymatic conjugation. This new technology enables the generation of a homogenous and site-specific DAR 2 ADC with unique biophysical properties. TUB-010 demonstrates similar binding and lysosomal release characteristics as Adcetris, which translates into comparable in vitro cytotoxicity on CD30-positive cell lines when normalized to the MMAE concentration. Importantly, TUB-010 exhibits higher stability with neglectable premature deconjugation in circulation and reduced aggregation as well as lower non-specific cytotoxicity on target-negative cells compared to Adcetris. As a consequence, TUB-010 induces superior tumor control compared to Adcetris when dosed at equal MMAE concentrations in vivo and also lower toxicity and higher tolerability in rodents and non-human primates. Taken together, TUB-010 is a novel, potential best-in-class anti-CD30 ADC with improved biophysical properties designed to deliver MMAE with higher precision and a wider therapeutic window than Adcetris using Tub-tag technology. Therefore, TUB-010 may increase the clinical benefit of anti-CD30 ADC therapies.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0062
  9. Nat Commun. 2025 Aug 21. 16(1): 7793
      Strategies targeting leukemic stem and progenitor cells (LSPCs) are needed for durable remissions in acute myeloid leukemia (AML) and high-risk myelodysplastic neoplasms (MDS). While CD123 constitutes a promising target on LSPCs and leukemic blasts, previous CD123-targeting approaches showed limited efficacy and challenging safety profiles. Here, we describe the preclinical efficacy and safety of the bispecific CD123/CD16A innate cell engager "AFM28", demonstrating superior activity against AML and MDS patient-derived LSPCs and blasts in vitro compared to an Fc-enhanced CD123-targeting antibody, especially towards CD123low and/or CD64+ leukemic cells. AFM28 induces autologous anti-leukemic activity in fresh AML whole blood cultures, demonstrating its potential to enhance NK cell function from AML patients. Responsiveness can be further enhanced by allogeneic NK cell addition. Anti-leukemic activity of AFM28 is confirmed in xenograft mouse models. In addition, AFM28 is well tolerated and demonstrates pharmacodynamic activity in cynomolgus monkeys. Altogether, our results indicate that AFM28 has the potential to reduce relapse-inducing residual disease and promote long-term remissions for patients with AML and MDS with a favorable safety profile.
    DOI:  https://doi.org/10.1038/s41467-025-63069-y
  10. Cells. 2025 Aug 15. pii: 1263. [Epub ahead of print]14(16):
      Despite the increasing number of novel therapies to treat newly diagnosed multiple myeloma (NDMM), preventing skeletal-related events (SREs) remains a challenge. This review summarizes the mechanistic causes of myeloma bone disease, data supporting the use of bisphosphonates and RANKL inhibitors, and the optimal management of preventing SREs in NDMM patients. Both zoledronic acid (ZA) and denosumab are acceptable treatment options with comparable safety and efficacy profiles. However, in patients who are candidates for autologous stem cell transplant (ASCT), denosumab may be preferred over ZA due to a progression-free survival (PFS) benefit observed in post hoc analyses when used with proteasome inhibitor-based regimens. The optimal duration of bone-directed therapy is unclear, but it is typically given for two years. Supportive care should include dental evaluation at baseline, annually, and if symptoms appear, given the risk for jaw osteonecrosis with both ZA and denosumab. Both drugs should be held in the setting of dental work. Patients should receive adequate calcium and vitamin D supplementation. Supportive procedures such as cement augmentation, radiation, and orthopedic surgery can also help treat compression fractures, uncontrolled pain, cord compression, and pathologic fractures. We conclude with our approach for managing SREs and a review of novel therapies and targets.
    Keywords:  denosumab; multiple myeloma; skeletal-related events; zoledronic acid
    DOI:  https://doi.org/10.3390/cells14161263
  11. Clin Exp Med. 2025 Aug 23. 25(1): 301
      Extramedullary involvement (extramedullary disease, EMD) is an aggressive subtype of multiple myeloma (MM) characterized by myeloma subclones proliferating independently of the bone marrow microenvironment, often associated with high-risk cytogenetic abnormalities, immune evasion, and treatment resistance. While significant breakthroughs have been achieved in MM treatment with the sequential approval of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, prognosis remains poor once EMD develops. Even in the era of immunotherapy, the survival benefit for EMD patients has not shown significant improvement. This review systematically summarizes therapeutic options for MM patients with EMD, aiming to provide evidence-based guidance for EMD treatment.
    Keywords:  Extramedullary disease; Immunotherapy; Multiple myeloma; Targeted therapy
    DOI:  https://doi.org/10.1007/s10238-025-01821-w
  12. Antibodies (Basel). 2025 Aug 01. pii: 65. [Epub ahead of print]14(3):
      Antibody-mediated autoimmune diseases are common, can involve any organ system, and pose a large burden for patients and healthcare systems. Most antibody-mediated diseases are mediated by IgG antibodies. Selective targeting of pathogenic antibodies is an attractive treatment option which has already proven to be effective in antibody-positive generalized myasthenia gravis, maternal-fetal alloimmune cytopenias, and immune thrombocytopenic purpura. Warm autoimmune hemolytic anemia (wAIHA) is an autoimmune disorder mediated by pathogenic antibodies mainly of the IgG class with no approved therapy. Current treatment includes non-specific immunosuppression with corticosteroids, rituximab, and other immunosuppressive agents. With most therapies, time to response can be delayed and transfusions may be needed. Neonatal Fc receptor (FcRN) therapies provide rapid and sustained reduction of pathogenic IgG levels providing potential for fast, effective therapy in antibody-mediated autoimmune diseases including warm autoimmune hemolytic anemia. This review focuses on the emerging role of FcRn inhibition in autoimmune hematologic diseases, and their therapeutic potential in wAIHA.
    Keywords:  FcRn blocker; FcRn inhibitor; warm autoimmune hemolytic anemia
    DOI:  https://doi.org/10.3390/antib14030065
  13. Blood. 2025 Aug 20. pii: blood.2025029987. [Epub ahead of print]
      Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, but also on what treatment patients received. To establish the true incidence of FHR, we analysed uniformly treated, transplant-eligible (TE) patients from the UK NCRI Myeloma-XI trial that had been profiled for IMS/IMWG defined high-risk cytogenetic aberrations (HRCA) and the SKY92 gene expression HR signature (GEP-HR). 135 TE MyXI patients meeting these criteria were studied, with a median follow-up of 88 months. 25 patients (18.5%) experienced ER, defined as relapse <18 months from maintenance randomization post-autologous stem-cell transplantation. Hereof, 15 (60%) were classified as IMS/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS/IMWG-HR. Among 4 patients with both IMS/IMWG- & GEP-standard risk (SR), 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR criteria. The combination of IMS/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS/IMWG-HR and GEP-HR was associated with very short overall survival compared to the absence of both (HR=13.1, 95%-CI: 6.5-26.1, P<0.0001), followed by GEP-HR only (HR=5.1, 95%-CI: 2.4-11.1, P<0.0001) and IMS/IMWG-HR only (HR=3.2, 95%-CI: 1.6-6.2, P=0.0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. ISRCTN49407852, NCT01554852.
    DOI:  https://doi.org/10.1182/blood.2025029987
  14. EJHaem. 2025 Aug;6(4): e70070
       Background: Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, is a promising treatment for blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is currently under evaluation in clinical trials. However, several case reports have reported relapses after prolonged treatment, and development of resistance. To date, no study has investigated resistance to venetoclax in BPDCN. Therefore, we sought to investigate the mechanisms that trigger resistance during treatment.
    Methods: We developed an in vitro model of chronic exposure of a BPDCN cell line to venetoclax that leads to resistance to the drug. We then characterized the resistant cell line using genomic and proteomic analyses and evaluated drug combinations to overcome the resistance.
    Results: We found an upregulation of BCL-xL, both at genomic and protein levels in the resistant BPDCN cell line. By combining venetoclax with a hypomethylating agent, we were able to overcome venetoclax resistance and induce resistant cell-line death. However, association with a proteasome inhibitor, known to be efficient against BPDCN, failed to restore sensitivity to venetoclax, probably due to modification of the NF-κB pathway observed by bulk-RNAseq analysis.
    Conclusions: Collectively, these data suggest that acquired venetoclax resistance in BPDCN is mediated by a modification of the balance of BCL-2 family proteins. Also, the mechanisms involved in resistance may also lead to resistance to other molecules among the drugs that might otherwise have been considered as alternative therapies.
    Clinical Trial Registration Including Trial Number: The authors have confirmed clinical trial registration is not needed for this submission.
    DOI:  https://doi.org/10.1002/jha2.70070
  15. Blood. 2025 Aug 26. pii: blood.2025028642. [Epub ahead of print]
      The discovery of calreticulin (CALR) mutations in patients with myeloproliferative neoplasms (MPN) has paved the way for the elucidation of a unique disease mechanism that is particularly well-suited to targeting by biologics. All MPN-associated pathogenic CALR mutations are characterized by a frameshift, resulting in translation of the same neoantigen peptide. This neoantigen directly activates the thrombopoietin receptor, leading to uncontrolled neoplastic cell proliferation. Current therapeutic approaches for MPN are focused primarily on blood count control. Furthermore, current approaches are neither disease-modifying nor clonally selective. However, as the mutant CALR neoantigen peptide is functional and not expressed in normal physiology, it is an ideal drug target. Here, we review the structure and function of mutant CALR, including the subtle yet clinically and therapeutically relevant differences between the two most commonly occurring types of mutation. We also review the current therapeutic landscape for CALR-mutated MPN, highlighting the areas in which current approaches are inadequate. Finally, we review ongoing clinical and preclinical experimental approaches for targeting mutant CALR in MPN in a clonally selective manner using monoclonal antibodies, bispecific antibodies, cancer vaccination, chimeric antigen receptor T cells, and antibody-drug conjugates. Taken together, we expect that ongoing developments in mutant CALR-targeted therapeutics will lead to promising novel strategies for long-term disease control.
    DOI:  https://doi.org/10.1182/blood.2025028642
  16. Cancer. 2025 Sep 01. 131(17): e70053
       BACKGROUND: Venetoclax (VEN) in combination with azacitidine (AZA) (VEN-AZA) is used to treat acute myeloid leukemia (AML) in patients who are not candidates for intensive chemotherapy but research on prognostic factors remains limited.
    METHODS: Measurable residual disease (MRD) by multiparametric flow cytometry in AML is important but there is limited evidence of the clinical utility of monitoring MRD in patients treated with VEN-AZA. Herein, a total of 75 patients newly diagnosed with AML treated with VEN-AZA were retrospectively analyzed to examine the role and timing of MRD to predict survival. MRD enabled the categorization of patients into two groups: Day 14 MRD, >1% (MRD14-pos); and Day 14 MRD, ≤1% (MRD14-neg).
    RESULTS: Of the 75 patients, 31 (41.3%) had MRD14-neg, whereas 30 (40.0%) had not achieved complete remission (CR) after induction. MRD14-neg was associated with improved overall survival (OS) (p = .024) and event-free survival (EFS) (p = .044). In addition, MRD14-neg (p = .002 for both OS and EFS), CSF3R negative (CSF3Rneg) (p < .001 for both OS and EFS), and transplantation (p = .005 for OS; p = .007 for EFS) were associated with improved survival outcomes. Further subgroup analysis revealed that MRD14-pos patients who underwent transplantation showed a trend toward longer OS and EFS (p < .001 for both).
    CONCLUSIONS: Results in the MRD14-neg group were better than in the MRD14-pos group, and the prognosis for patients with AML was better when there was CSF3Rneg and transplantation. Additionally, for patients with AML with MRD14-pos, consolidation with transplantation may increase survival.
    Keywords:  CSF3R; acute myeloid leukemia; azacitidine; measurable residual disease (MRD); transplantation; venetoclax
    DOI:  https://doi.org/10.1002/cncr.70053
  17. Intern Med. 2025 Aug 28.
      Plasmablastic lymphoma (PBL) is a rare and aggressive B-cell lymphoma with a poor prognosis and is typically linked to HIV-related immunodeficiency. PBL associated with ulcerative colitis (UC) is an extremely rare condition. We report the case of a 63-year-old HIV-negative woman with UC who developed colonic PBL after long-term mesalazine and budesonide treatment. She achieved complete remission following chemotherapy and abdominal radiotherapy, with no recurrence for more than three years. To our knowledge, this is the fourth reported case of UC-associated PBL and demonstrates the longest survival. Chemoradiotherapy may be an effective treatment for localized PBL.
    Keywords:  Chemoradiotherapy; Colonic lymphoma; Plasmablastic lymphoma; Ulcerative colitis
    DOI:  https://doi.org/10.2169/internalmedicine.5964-25
  18. Ann Hematol. 2025 Aug 27.
      The adoption of pediatric-inspired regimens for the treatment of Ph-negative acute lymphoblastic leukemia (ALL) in adults has improved prognosis. However, the feasibility of these intensive regimens in older patients is limited, due to the increased incidence of therapy-related side effects, including those related to asparaginase. In this sub-analysis carried out by the Campus ALL network, 90 ALL patients aged 55 or more (median age 59 years) homogeneously treated in real-life according to the GIMEMA LAL1913 program, were analyzed to evaluate the feasibility and tolerability of pegaspargase (PEG-ASP) treatment. Among the 90 patients analyzed, 86 (96%) received PEG-ASP at least in one of the first two courses (C1-C2) of chemotherapy and were evaluated for toxicity and outcome. In detail, 51 patients received PEG-ASP in both courses and 35 in either C1 or C2. The most common adverse event was hepatic toxicity (HT), with 38% of patients experiencing any grade of HT at C1 (HT grade ≥ 3, 19%) and 23% at C2 (HT grade ≥ 3, 9%). Additionally, HT at C1 was the primary reason for withholding PEG-ASP at C2. Coagulopathy was the second most frequent toxicity (any grade of toxicity in 26% of patients at C1 and in 20% at C2). No deaths directly related to PEG-ASP therapy were reported. The CR rate after C1 and C3 was 94% and 93%, respectively. MRD negativity rate was 40% and 68%, respectively. The OS and DFS probability at 3 years was 54% and 47%, respectively. PEG-ASP administration in older ALL patients is feasible, but HT is a concern, being the major cause of PEG-ASP interruption. Therefore, a dose adjustment, according to age and concomitant comorbidities, is advisable to balance PEG-ASP efficacy with its toxicity.
    Keywords:  Acute lymphoblastic leukemia; Older patients; Pegaspargase; Real-life study
    DOI:  https://doi.org/10.1007/s00277-025-06550-4
  19. N Engl J Med. 2025 Aug 21. pii: 10.1056/NEJMc2509175#sa1. [Epub ahead of print]393(8):
      
    DOI:  https://doi.org/10.1056/NEJMc2509175
  20. Oncol Rev. 2025 ;19 1482866
      Despite increases in prevalence, many cutaneous T-cell lymphoma (CTCL) patients still lack effective and safe therapies for their disease. The most prevalent subtype, mycosis fungoides is usually managed with skin directed treatments in early stages, while advanced stages are often targeted with systemic medications. These treatments are all symptomatic except for allogeneic hematopoietic stem cell transplantation, which is associated with its own risks of relapse and potentially fatal complications. A novel class of drugs termed "JAK inhibitors" (JAKi) has recently been developed primarily for chronic inflammatory diseases, but there is substantial evidence of JAK/STAT pathway overactivation also in CTCL. As of 1 December 2024, 14 JAKis have been collectively approved by the European Medicines Agency, the Food and Drug Administration and the Pharmaceutical and Medical Devices Agency of Japan. Despite some evidence from case reports, the efficacy and safety of JAKi in CTCL remains to be determined in controlled clinical trials. This review summarizes the current evidence on pathogenic JAK activation and its potential therapeutic inhibition in CTCL.
    Keywords:  CTCL; JAK inhibition; Sezary syndrome; lymphoma; mycosis fugoides
    DOI:  https://doi.org/10.3389/or.2025.1482866
  21. Ther Adv Med Oncol. 2025 ;17 17588359251363207
      The heterogeneity of lymphoma responses to various treatments remains a significant challenge in clinical practice. Emerging evidence implicates the potential role of the gut microbiome in lymphoma pathogenesis and progression. Advances in high-throughput sequencing and metabolomics have significantly enhanced our understanding of the complex interaction between the gut microbiome and lymphoma. Although causality requires further elucidation, the gut microbiome critically shapes host responses to traditional combined chemotherapy, hematopoietic stem cell transplantation, and targeted therapies, including chimeric antigen receptor T-cell therapy. Notably, the use of antibiotics, particularly broad-spectrum antibiotics, can alter the gut microbiome, thereby impacting treatment efficacy. Prudent antibiotic management should balance infection control with microbiome-dependent immune homeostasis. Strategies to restore gut microbial balance through a high-fiber diet, probiotics, prebiotics, fecal microbiota transplantation, and butyrate supplementation are critically important. Integrating microbiome-based therapies into lymphoma treatment could establish low-toxicity therapeutic paradigms for lymphoma patients.
    Keywords:  antibiotic management; gut metabolites; gut microbiome; lymphoma; microbiome therapy
    DOI:  https://doi.org/10.1177/17588359251363207
  22. Clin Exp Med. 2025 Aug 22. 25(1): 300
    Japanese Society of Transplantation and Cellular Therapy
      VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) is a recently identified clonal disorder caused by somatic UBA1 mutations in hematopoietic stem cells, leading to bone marrow failure (BMF) and systemic inflammation. We screened 1771 patients with BMF who underwent unrelated hematopoietic cell transplantation in Japan between 1995 and 2020 using multitarget real-time PCR. The diagnoses included myelodysplastic syndrome (MDS, n = 1139), myeloproliferative neoplasms (n = 125), plasma cell neoplasms (n = 23), acquired BMF (n = 395), and congenital BMF (n = 89). Pathogenic UBA1 mutations were detected in two male patients with MDS (aged 48 and 63 years), corresponding to a prevalence of 0.11% in the overall cohort and 0.18% in MDS cases; an additional 70-year-old male was diagnosed outside of the cohort. All three underwent unrelated bone marrow transplantation following fludarabine and busulfan-based conditioning. The first and third patients died of idiopathic pneumonia syndrome 5 and 28 months after transplantation. In the third patient, UBA1-mutant cells persisted at low frequency in skin graft-versus-host disease tissue despite clearance from his blood. The second patient survived without relapse or graft-versus-host disease at 28 months. Although VEXAS syndrome is rare among unrelated HCT recipients with malignant and non-malignant BMF in the historical cohort, HCT is positioned as a potentially curative, yet high-risk strategy. Additional studies are essential to refine patient selection, optimize transplant timing, and improve management strategies to mitigate risk and enhance survival. Therefore, the role of tissue-residual UBA1-mutant clones in post-transplant complications warrants further investigation.
    Keywords:   UBA1 mutation; Allogeneic hematopoietic cell transplantation; Bone marrow failure; Myelodysplastic syndrome; VEXAS syndrome
    DOI:  https://doi.org/10.1007/s10238-025-01832-7