bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–09–06
33 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Functional characterization of snoRNA-derived RNA (sdRNA) expression in healthy hematopoiesis and acute myeloid leukemia.
  2. Csnk1a1 E98 mutations rewire signaling and metabolism in del(5q) myelodysplastic neoplasms.
  3. Defining and predicting disease progression in myeloproliferative neoplasms: a proposed biomarker-driven approach.
  4. Comparison of venetoclax and azacitidine versus a cytarabine-based treatment for patients with acute myeloid leukaemia in first relapse after chemotherapy. A real-world study of the DATAML-IPC-AURAML consortium.
  5. Overall survival and long-term outcomes from the randomized, double-blind, placebo-controlled, phase III IMerge trial of imetelstat for lower-risk myelodysplastic syndromes.
  6. Characterisation of TP53 mutational features and outcomes of acute myeloid leukaemia after allogeneic haematopoietic cell transplantation.
  7. Allogeneic stem cell transplantation with post-transplantation cyclophosphamide in patients with acute myeloid leukemia achieving first complete remission after one versus two inductions: a study from the ALWP/EBMT.
  8. Choice of hypomethylating agent for newly diagnosed TP53-mutant acute myeloid Leukemia: a COMMAND registry study.
  9. XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia.
  10. Non-genetic remodeling drives leukemia propagation and reveals actionable vulnerabilities in acute myeloid leukemia.
  11. Cusatuzumab combined with venetoclax with or without azacitidine in unfit patients with newly diagnosed acute myeloid leukemia: phase Ib ELEVATE study.
  12. AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness.
  13. Vitamin C promotes differentiation of stress-specific erythroid progenitors in stress erythropoiesis.
  14. Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity.
  15. Therapy-persistent leukemia is selectively vulnerable to SLC23A1 restoration via targeting KHSRP.
  16. FLT3-directed therapy in acute myeloid leukemia: lessons from the final analysis of LACEWING.
  17. Real-World Outcomes of Midostaurin Plus Intensive Chemotherapy in FLT3-Mutated AML: The PETHRATIFY Study.
  18. A step-wise, deterministic and fatal mouse model of myeloid neoplasm with spontaneous acquisition of patient-relevant RTK-RAS mutations.
  19. Germline noncoding risk variants influence clonal hematopoiesis through altered hematopoietic enhancer activity.
  20. Bone marrow stromal cells promote chemoresistance in acute myeloid leukaemia through P2RX7-mediated antioxidant defence.
  21. Gilteritinib plus azacitidine in patients with newly diagnosed FLT3 mutation-positive acute myeloid leukemia who were ineligible for intensive chemotherapy: final results of the phase III LACEWING study.
  22. Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.
  23. KLF4/MLL3 complex axis drives NRBP2 transcription to eliminate acute myeloid leukemia cells.
  24. Treatment-free remission in CML patients with prior TKI failure is not influenced by previous BCR::ABL1 kinase domain mutations.
  25. Azacitidine-Venetoclax or Induction Chemotherapy for Acute Myeloid Leukemia.
  26. Timing of response in patients with relapsed/refractory FLT3 mut+ acute myeloid leukemia treated with gilteritinib.
  27. The type I FLT3 inhibitor XL999 overrides secondary FLT3-ITD mutations that arise under gilteritinib and quizartinib treatment in acute myeloid leukemia.
  28. Leveraging venetoclax-induced autophagy to enhance AUTAC-mediated Mcl1 degradation and overcome resistance in acute myeloid leukaemia.
  29. Association of sarcopenia with treatment tolerance in older adults with acute myeloid leukemia using artificial intelligence computed tomography-segmentation and a geriatric assessment.
  30. Allele burden expansion in JAK2 V617F and CALR-mutated myeloproliferative neoplasms predicts disease progression and is associated with anagrelide treatment.
  31. Infection risk in myelodysplastic syndromes is dynamic and immune driven.
  32. Development and validation of a machine learning model based on routine laboratory tests for predicting FLT3-ITD mutations in acute myeloid leukaemia.
  33. Incidence, prevalence, and survival outcomes of patients with myeloproliferative neoplasms in the United States: a Surveillance, Epidemiology, and End Results (SEER) database analysis, years 2000-2021.
  1. Leukemia. 2026 Sep 04.
    Functional characterization of snoRNA-derived RNA (sdRNA) expression in healthy hematopoiesis and acute myeloid leukemia.
    Rafael Zinz, Christian Rohde, Cornelius Pauli, Fengbiao Zhou, Azmal Ali Syed, Daniel Heid, Viral Shah, Niklas Alexander Wahl, Adrija Ray, Simon Renders, Laura Werner, Sandra Förmer, Carl Ahrens, Claudia Baldus, Martin Bornhäuser, Christoph Röllig, Hubert Serve, Tim Sauer, Jeroen Krijgsveld, Carsten Müller-Tidow, Maximilian Felix Blank.
      SnoRNAs are highly expressed in AML and have implications in leukemogenesis and leukemic maintenance. SnoRNAs can be further processed into snoRNA-derived RNAs (sdRNAs). The role of sdRNAs in AML and healthy hematopoiesis remains largely elusive. We characterized sdRNA and snoRNA levels in hematopoietic stem and progenitor cells (HSPCs), healthy WBCs, and 159 intensively treated AML patient samples at initial diagnosis. HSPCs, healthy WBCs, and AML blasts could be differentiated by their sdRNA expression pattern in a cell-type-specific manner. In AML, high sd3'-RNA/snoRNA-host gene ratios were associated with an inverse patient outcome. Particularly, in NPM1-mutated patients with favorable risk stratification and good initial therapy response, high sd3'-RNA ratios identified a subgroup with inferior outcome. High sd3'-RNA ratios were associated with altered oncogenic, inflammatory, and immune response signaling. Forced expression of single sdRNAs, such as sd3'-SNORD78, sd3'-SNORD76, and sd5'-SNORD93, enhanced clonogenic potential in AML and drove sdRNA-specific gene expression signatures in both AML and healthy HSPCs. Exemplarily, we propose and characterize NUDT21, an important regulator of alternative polyadenylation and oncogenic gene expression, as a downstream target of sd3'-SNORD78 in AML. Our data introduce sdRNAs as standalone regulatory effector molecules in healthy hematopoiesis and AML.
    DOI:  https://doi.org/10.1038/s41375-026-03120-z
  2. Leukemia. 2026 Sep 03.
    Csnk1a1 E98 mutations rewire signaling and metabolism in del(5q) myelodysplastic neoplasms.
    Stephani Schmitz, Juliette E Pearce, Sergio Martinez-Høyer, Gerjanne Vroeg In de Wei, Inge A M Snoeren, Ursula S A Stalmann, Stijn N R Fuchs, Aurelien J F Dugourd, Giulia Franciosa, Eric M Bindels, Wencke Walter, Claudia Meyer, Torsten Haferlach, Emiel P C van der Vorst, Oriol Calvete, Francesc Solé, Julio Saez-Rodriguez, Andreas Linkermann, Jesper Olsen, Hélène F E Gleitz, Rebekka K Schneider.
      Deletion of chromosome 5q [del(5q)] is the most common cytogenetic abnormality in myelodysplastic neoplasms (MDS) and results in haploinsufficiency of multiple genes, including CSNK1A1. Recurrent CSNK1A1 mutations, predominantly affecting the E98 hotspot, occur almost exclusively in del(5q) MDS and are associated with adverse outcomes, yet their impact on CK1ɑ function remains unclear. Using integrated transcriptomic, (phospho)proteomic, and kinome activity profiling in hematopoietic stem and progenitor cells (HSPCs), combined with in vivo serial transplantation assays, we show that Csnk1a1 E98V represents a change-of-function rather than a loss-of-function mutation. Unlike Csnk1a1 haploinsufficiency, Csnk1a1 E98V preserves long-term hematopoietic reconstitution and does not enhance clonal expansion in vivo. Instead, the mutation induces suppression of kinase signaling networks, leading to coordinated repression of ribosomal gene expression, protein translation, and cell cycle programs. This signaling rewiring is accompanied by metabolic reprogramming characterized by reduced mitochondrial respiration, increased glycolytic flux, and an inability to adapt to metabolic challenges, creating a stress-tolerant but inflexible cellular state. Notably, Csnk1a1 E98V cells exhibit impaired megakaryopoiesis and increased vulnerability to iron overload, as well as RSL-3-mediated ferroptosis. Analysis of del(5q) MDS patients confirmed that CSNK1A1 mutations are associated with distinct clinical features, including thrombocytopenia, elevated myeloblasts, and reduced bone marrow iron levels. Together, our findings support a two-step model in which del(5q)-associated CSNK1A1 haploinsufficiency drives clonal expansion, followed by acquisition of CSNK1A1 mutations that promote stress tolerance rather than increased proliferation. This adaptive rewiring exposes metabolic and iron-dependent vulnerabilities that may be therapeutically exploited.
    DOI:  https://doi.org/10.1038/s41375-026-03122-x
  3. Leukemia. 2026 Sep 01.
    Defining and predicting disease progression in myeloproliferative neoplasms: a proposed biomarker-driven approach.
    Raajit K Rampal, Richard Winneker, Andrew Kuykendall, Laura C Michaelis, Ghaith Abu-Zeinah, Steffen Koschmieder, Jan Philipp Bewersdorf, Zi Yun Ng, Gabriella Hobbs, Bridget Marcellino, Linda Resar, Joseph Scandura, Anand Patel, John Mascarenhas, Aaron Gerds, Douglas Tremblay, Shane Mayack, Andriy Derkach, Florian H Heidel.
      
    DOI:  https://doi.org/10.1038/s41375-026-03103-0
  4. Br J Haematol. 2026 Sep 04.
    Comparison of venetoclax and azacitidine versus a cytarabine-based treatment for patients with acute myeloid leukaemia in first relapse after chemotherapy. A real-world study of the DATAML-IPC-AURAML consortium.
    Pierre-Yves Dumas, Sarah Bertoli, Emilie Bérard, Clémence Santana, Maël Heiblig, Thibaut Leguay, Suzanne Tavitian, Estelle Borgne, Anne-Charlotte de Grande, Audrey Sarry, Ziyad Acheaibi, Laetitia Largeaud, Morgane Sighieri, Emilie Klein, Emmanuelle Tavernier, Marie-Anne Hospital, Martin Carré, Gaspar Aspas Requena, Anne Banos, Norbert Vey, Arnaud Pigneux, Christian Récher, Sylvain Garciaz.
      Complete remission (CR) rates for patients with acute myeloid leukaemia (AML) treated with intensive chemotherapy (IC) have increasingly improved. Yet, relapse remains a concern with a dismal prognosis. In this report, results are presented of a retrospective analysis comparing salvage therapy based on intermediate (I) or high (H)-dose cytarabine (DAC) (n = 203) and venetoclax-azacitidine (VEN-AZA) (n = 114) for patients with AML in first relapse. Patients (median age 60 years, interquartile range [IQR] 48-67) had reached CR1 after a standard 7 + 3 (n = 305) or CPX351 schedule (n = 12). I/HDAC-based and VEN-AZA salvage, respectively, resulted in CR2 in 66.0% and 66.7% of the patients (p = 0.96). Allogeneic haematopoietic stem cell transplantation (allo-HSCT) was performed for 115 patients in CR2 and 18 in failure. Relapse-free survival was 13.2 (IQR 7.0-not reached [NR]) and 13.7 (IQR 7.8-NR) months while overall survival (OS) was 14.5 (IQR 6.2-NR) and 12.3 months (IQR 4.8-NR; p = 0.41) for patients who received I/HDAC-based salvage and VEN-AZA respectively. In multivariable analysis, relapsing patients ≥60 years with low/intermediate-risk cytogenetics and VEN-AZA had a better OS (p = 0.002), while I/HDAC was more efficient for those with poor risk cytogenetics and < 60-year-old (p = 0.002). VEN-AZA salvage therapy thus appears promising compared with conventional I/HDAC-based IC; this question warrants evaluation in randomized studies.
    Keywords:  acute myeloid leukaemia; azacitidine; cytarabine; first relapse; real‐life; venetoclax
    DOI:  https://doi.org/10.1111/bjh.70815
  5. Haematologica. 2026 Sep 03.
    Overall survival and long-term outcomes from the randomized, double-blind, placebo-controlled, phase III IMerge trial of imetelstat for lower-risk myelodysplastic syndromes.
    Valeria Santini, Rami S Komrokji, Michael R Savona, María Díez-Campelo, Pierre Fenaux, Mikkael A Sekeres, Yazan F Madanat, David Valcárcel, Anna Jonášová, Petra Belohlavkova, Tymara Berry, Souria Dougherty, Sheetal Shah, Qi Xia, Libo Sun, Ying Wan, Fei Huang, Faye Feller, Shyamala Navada, Amer M Zeidan, Uwe Platzbecker.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.301456
  6. Bone Marrow Transplant. 2026 Sep 04.
    Characterisation of TP53 mutational features and outcomes of acute myeloid leukaemia after allogeneic haematopoietic cell transplantation.
    Martina Reuss, Thomas Meyer, Florian Ingelfinger, Rouven Hoefflin, Miriam Mozaffari Jovein, Hosna Baniadam, Dietmar Pfeifer, Justus Duyster, Jesus Duque-Afonso, Kristina Maas-Bauer, Ralph Wäsch, Armin Zebisch, Annkristin Heine, Tobias Holderried, Jürgen Finke, Claudia Wehr, Robert Zeiser, Tobias Wertheimer.
      TP53 mutations define a clinically distinct subset of acute myeloid leukaemia (AML) associated with complex cytogenetics and therapy resistance. We performed a retrospective single-centre analysis of 61 consecutive TP53-altered AML patients undergoing first allogeneic haematopoietic cell transplantation (allo-HCT) at the Medical Center Freiburg (2007-2025), compared with 636 TP53-wild-type controls. TP53-altered patients had markedly inferior overall survival (median 379 vs. 1694 days; 5-year OS 18% vs. 50%; p < 0.001). Excess relapse was the primary driver (5-year cumulative incidence 55% vs. 33%; p < 0.001), whereas non-relapse mortality did not differ (28.5% vs. 23%; p = 0.426). On multivariable Cox analysis, TP53 alteration was the strongest independent predictor of inferior OS (HR 2.54, 95% CI 1.77-3.64; p < 0.001), and this association persisted after adjustment for cytogenetic risk and for the refined Disease Risk Index. In an exploratory hierarchical clustering analysis extended by seven patients from a second centre, two subgroups emerged: a del(17p)-enriched cluster (n = 12; median OS 5.7 months) and a TP53 point mutation-enriched cluster (n = 56; median OS 15.1 months). TP53-altered AML is confirmed as the strongest independent adverse prognostic factor after allo-HCT, and molecular heterogeneity within this subtype may inform trial stratification and targeted post-transplant interventions.
    DOI:  https://doi.org/10.1038/s41409-026-03029-2
  7. Bone Marrow Transplant. 2026 Sep 02.
    Allogeneic stem cell transplantation with post-transplantation cyclophosphamide in patients with acute myeloid leukemia achieving first complete remission after one versus two inductions: a study from the ALWP/EBMT.
    Arnon Nagler, Ryszard Swoboda, Allain Thibeault Ferhat, Didier Blaise, Jurjen Versluis, Gwendolyn Van Gorkom, Maija Itala-Remes, Mercedes Colorado Araujo, Helene Labussiere-Wallet, Ibrahim Yakoub-Agha, Regis Peffault de Latour, Tobias Gedde-Dahl, Mieke W H Roeven, Edouard Forcade, Martin Carré, Patrice Chevallier, Deborah Desmier, Maurizio Musso, Jaime Sanz, Eolia Brissot, Ali Bazarbachi, Mohamad Mohty, Fabio Ciceri.
      Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative treatment for high-risk acute myeloid leukemia (AML), and outcomes are strongly influenced by disease status at transplantation. In transplants using conventional graft-versus-host disease (GVHD) prophylaxis, outcomes also depend on the number of induction courses required to achieve first complete remission (CR1); however, this has not been evaluated in patients receiving post-transplant cyclophosphamide (PTCy). We retrospectively analyzed 677 adult AML patients transplanted in CR1 between 2012 and 2022 using PTCy-based GVHD prophylaxis. Outcomes were compared between patients achieving CR1 after one induction course (n = 518) and those requiring two courses (n = 159). Baseline characteristics, donor type, conditioning intensity, graft source, engraftment, and rates of acute and chronic GVHD were comparable between groups. Patients requiring two inductions had a higher 2-year cumulative incidence of relapse (27% vs. 19.3%; HR 1.75, p = 0.003). However, no significant differences were observed in 2-year overall survival (62.8% vs. 69%), leukemia-free survival (61.1% vs. 65%), GVHD-free/relapse-free survival (46.3% vs. 50.4%), or non-relapse mortality (11.9% vs. 15.7%). In AML patients receiving alloHSCT with PTCy, outcomes were largely similar regardless of whether CR1 was achieved after one or two-induction courses, with relapse incidence being higher in patients requiring 2 inductions.
    DOI:  https://doi.org/10.1038/s41409-026-03012-x
  8. Leukemia. 2026 Aug 31.
    Choice of hypomethylating agent for newly diagnosed TP53-mutant acute myeloid Leukemia: a COMMAND registry study.
    Talha Badar, James Foran, Omer Jamy, Chenyu Lin, Anand Patel, Yu-Hung Wang, Mahesh Kumar, Rory M Shallis, Kendall Diebold, Alexander Coltoff, Aaron D Goldberg, Jan P Bewersdorf, Kenneth M Zabel, Charles Foucar, Yasmin Abaza, Guru S Murthy, Neil Palmisiano, Adam S DuVall, Vamsi Kota, Shyam A Patel, Amer M Zeidan, Hemant Murthy, Mohamed Kharfan-Dabaja, Ehab Atallah, Mark R Litzow.
      Although azacitidine (AZA) and decitabine (DEC) demonstrate comparable efficacy in AML, prior data suggest that DEC may induce deeper TP53 mutation clearance and higher response rates; however, direct comparisons in TP53-mutant (TP53-MT) AML are lacking. We conducted a large multicenter retrospective analysis to compare outcomes between DEC- and AZA-based induction, including combinations with venetoclax (VEN). Of 652 patients with newly diagnosed TP53-MT AML, 321 received HMA-based induction (DEC, n = 183; AZA, n = 138). Baseline clinical and genomic characteristics were comparable between the DEC and AZA groups. TP53 mutation subtype were not associated with outcomes, whereas multi-hit TP53 status was independently associated with inferior EFS and OS. In the propensity score-matched cohort, no significant differences in event-free survival (EFS; P = 0.920) or overall survival (OS; P = 0.927) were observed. Median EFS was 5.1, 3.4, 5.9, and 5.6 months, with 12-month estimates of 24%, 17%, 18%, and 16%, while median OS was 5.7, 7.1, 9.2, and 7.1 months, with corresponding 12-month OS rates of 31%, 23%, 29%, and 32% for DEC + VEN, AZA + VEN, DEC, and AZA, respectively. No significant pairwise differences were observed between regimens. These findings from a large multicenter cohort suggest that AZA- and DEC-based induction yield comparable survival outcomes in TP53-MT AML.
    DOI:  https://doi.org/10.1038/s41375-026-03119-6
  9. J Clin Invest. 2026 Sep 01. pii: e204701. [Epub ahead of print]
    XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia.
    Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang.
      Activating mutations in FMS-like tyrosine kinase 3 (FLT3) drive aggressive acute myeloid leukemia (AML) and confer poor prognosis. Although FLT3 inhibitors have improved outcomes, their efficacy is frequently limited by microenvironment-mediated signaling and treatment-emergent resistance. XY0206 is a structurally optimized derivative of sunitinib, an inhibitor approved for multiple solid tumors. Biochemical, multi-omics, and functional analyses showed that XY0206 directly engages FLT3 and suppresses downstream STAT5, AKT, and ERK signaling, resulting in apoptosis in FLT3-ITD AML cells. Across models of FLT3-dependent resistance, XY0206 retained antileukemic activity, including in FLT3-ITD cells harboring the F691L gatekeeper mutation, a recurrent alteration conferring resistance to approved FLT3 inhibitors. In primary AML blasts and xenograft models, XY0206 exhibited enhanced antileukemic activity with favorable tolerability relative to gilteritinib. In a phase I/II trial (NCT04471064) of XY0206 monotherapy in patients with relapsed or refractory (R/R) AML, XY0206 achieved a composite complete remission rate (CRc) of 45.7% overall, with a notable 60.0% CRc rate among patients with FLT3-ITD mutations. Three of eight patients with prior FLT3 inhibitor-exposed R/R AML also achieved CRc. Together, these findings support further clinical evaluation of XY0206 as a FLT3-directed therapeutic in AML, particularly in disease settings with reduced sensitivity to existing FLT3 inhibitors.
    Keywords:  Cell biology; Clinical Research; Clinical trials; Drug therapy; Hematology; Leukemias
    DOI:  https://doi.org/10.1172/JCI204701
  10. Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00434-9. [Epub ahead of print] 103017
    Non-genetic remodeling drives leukemia propagation and reveals actionable vulnerabilities in acute myeloid leukemia.
    Clement Larrue, Paolo Angelino, Sarah Mouche, Alexa S Green, Emeline Boet, Ismael Boussaid, Claudia Perez-Carretero, Rudy Birsen, Maxime Sajot, Thomas A Mckee, Ambrine Sahal, Nicolas Chapuis, François Vergez, Christian Recher, Véronique Mansat-De Mas, Olivier Kosmider, Pierre Sujobert, Frederic Catez, Jean-Jacques Diaz, Jean-Emmanuel Sarry, Petros Tsantoulis, Jerome Tamburini.
      Acute myeloid leukemia (AML) persistence and relapse are sustained by leukemia-propagating cells, yet the molecular programs supporting their expansion during disease evolution remain incompletely understood. Using serial patient-derived xenotransplantation, we establish a longitudinal model in which leukemia-initiating capacity progressively increases. Integrated single-cell transcriptomics and multi-omics profiling reveal a predominantly non-genetic trajectory that follows a conserved pattern across models and is associated with coordinated changes across epigenetic, transcriptional, and proteomic layers. Ribosome profiling and rRNA 2'-O-methylation analyses further support a stage-specific increase in translational activity with ribosome remodeling in advanced xenografts. A pharmacological screen of 3,247 compounds uncovers a limited set of vulnerabilities that consistently emerge during disease progression, including CRBN-dependent degradation of GSPT1 (CC-885) and IAP antagonism (AZD5582). In vivo validation shows that both agents markedly reduce leukemic burden, impair leukemia propagation, and enhance cytarabine activity in patient-derived xenograft (PDX) models. Together, these findings show that leukemic propagation is driven by a non-genetic remodeling program, providing a framework to prioritize and test stage-specific therapeutic strategies in AML.
    Keywords:  DNA methylation; acute myeloid leukemia; drug screening; leukemic stem cells; patient-derived xenografts; ribosome profiling; serial xenotransplantation; translational regulation
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103017
  11. Haematologica. 2026 Sep 03.
    Cusatuzumab combined with venetoclax with or without azacitidine in unfit patients with newly diagnosed acute myeloid leukemia: phase Ib ELEVATE study.
    Gail J Roboz, Thomas Pabst, Ahmed Aribi, Joseph M Brandwein, Hartmut Döhner, Walter Fiedler, Carsten Riether, Domenica Gandini, Michelle Geddes, Jing-Zhou Hou, Karen Yee, Anna Hultberg, Eric Huselton, Julie Jacobs, Piotr Zabrocki, Ewa Lech-Marańda, Marieke Louwers, Kerri Nottage, Uwe Platzbecker, Raajit Rampal, Masha Salman, Priya Shah, Kayla Wilson, Monic Stuart, Marion Subklewe, Anne Sumbul, Eunice S Wang, Agnieszka Wierzbowska, Bin Yao, Ravi Patel, Adam George, Nazmul Islam, Clay Smith, Michael Boyiadzis, Gautam Borthakur.
      Cusatuzumab is a monoclonal antibody that binds with high affinity to CD70, a cell surface protein overexpressed on CD34+ acute myeloid leukemia (AML) progenitors and leukemia stem cells. This phase Ib study assessed the safety, tolerability and efficacy of adding cusatuzumab to standard-of-care azacitidine and venetoclax (CVA) or a cusatuzumab and venetoclax (CV) doublet regimen in patients newly diagnosed with AML who were ineligible for intensive chemotherapy. Cusatuzumab 20 mg/kg was administered intravenously on days 3 and 17 of 28-day cycles combined with standard dosing of venetoclax ± azacitidine. Overall, 44 patients were treated with CVA. Common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (77.3%), thrombocytopenia (77.3%) and anemia (45.5%); non-hematologic TEAEs included nausea (45.5%), diarrhea (43.2%), constipation (40.9%), fatigue (36.4%) and vomiting (31.8%). Grade ≥3 infectious complications included febrile neutropenia (38.6%), sepsis (36.4%) and pneumonia (9.1%). The overall composite response rate (complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi]) was 77.3% (CR, 47.7%; CRh, 20.5%; CRi, 9.1%). Among CR/CRi responders, 53% achieved negative measurable residual disease by multiparameter flow cytometry. Median overall survival was 12.0 months (95% confidence interval: 8.7-NE) months. Sixteen patients were treated with CV and had similar safety but less favorable responses and survival than those treated with CVA. These results support further development of CVA for the treatment of AML (clinicaltrials.gov identifier: NCT04150887).
    DOI:  https://doi.org/10.3324/haematol.2026.300917
  12. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2608310123
    AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness.
    Shuyi Li, Shujiao He, Yongwei Su, Lei Wang, Yiran Wang, Yuanyuan Xu, Li Yu, Jingfeng Zhou.
      Chromosomal translocations produce oncogenic fusion proteins such as AML1-ETO, which predominantly occupy gene promoters to induce transcriptional reprogramming in leukemia stem cells (LSCs), consequently driving the pathogenesis of t(8;21) acute myeloid leukemia (AML). However, whether AML1-ETO is recruited to additional regulatory DNA elements to orchestrate oncogenic gene expression programs has not been fully addressed. Here, we define AML1-ETO and H3K27ac CUT&Tag landscapes in primary t(8;21) AML CD34+ cells and t(8;21) AML cell lines, revealing AML1-ETO binding at a distal enhancer of the RNA N4-acetylcytidine (ac4C) writer N-acetyltransferase 10 (NAT10), thereby driving its transcriptional activation. Genetic ablation or pharmacological inhibition of NAT10 restricted the survival and self-renewal of LSCs in primary t(8;21) AML CD34+ cells, as well as in a retroviral AML1-ETO9a-driven t(8;21) AML mouse model, establishing NAT10 as a potential therapeutic vulnerability. Mechanistically, NAT10 is recruited to glutathione S-transferase omega 2 (GSTO2) mRNA to catalyze ac4C modification, thereby enhancing transcript stability and reprogramming glutathione metabolism, as demonstrated by ac4C profiling, RNA immunoprecipitation (RIP), and dCas13b-NAT10-based analyses. Silencing of GSTO2 in primary t(8;21) AML CD34+ cells decreased intracellular reduced glutathione (GSH) levels and compromised LSC survival and self-renewal, whereas GSTO2 overexpression or GSH supplementation largely rescued LSC maintenance following NAT10 loss. Collectively, these findings enrich and extend the understanding of AML1-ETO regulatory programs by linking distal enhancer activity to a NAT10-GSTO2 ac4C-GSH axis that integrates epigenomic, posttranscriptional, and metabolic reprogramming to sustain LSC stemness, highlighting this circuit as a potential therapeutic vulnerability in t(8;21) AML.
    Keywords:  AML1-ETO; NAT10; ac4C; leukemia stem cells; t(8;21)
    DOI:  https://doi.org/10.1073/pnas.2608310123
  13. Blood. 2026 Sep 02. pii: blood.2025032877. [Epub ahead of print]
    Vitamin C promotes differentiation of stress-specific erythroid progenitors in stress erythropoiesis.
    Hsi-Hsien Hsieh, Yue Ma, Andrew W DeVilbiss, Stefano Comazzetto, Indhumathy Subramaniyan, Ji Hyung Jun, Richard A Voit, Li Li, Michail Agathocleous, Lily Jun-Shen Huang.
      We discovered that vitamin C import through the vitamin C transporter SLC23A2 in stress-specific erythroid progenitors represents a key regulatory nexus in the recovery of the erythron. In response to erythroid stress, such as blood loss, Epo induces the expression of Slc23a2 in stress erythroid progenitor cells, increasing intracellular vitamin C levels and promoting their differentiation into erythroblasts. Vitamin C-induced erythroid differentiation is blocked by Slc23a2 deletion or in EpoR mutant mice unable to induce Slc23a2. Both mice show attenuated erythron recovery in stress. These defects are rescued by exogenous expression of either SLC23A2 or the related vitamin C transporter SLC23A1, but not by a transport-defective SLC23A2 mutant. Mechanistically, intracellular vitamin C promotes erythroid progenitor differentiation independently of its antioxidant activity. Instead, it regulates 2-oxoglutarate-dependent dioxygenases, TET2, KDM6A and ALKBH8, facilitating the upregulation of the master erythroid transcription factor GATA1. These findings identify vitamin C uptake as an Epo-licensed, rate-limiting determinant of stress erythropoiesis.
    DOI:  https://doi.org/10.1182/blood.2025032877
  14. Nat Commun. 2026 Sep 04. pii: 9151. [Epub ahead of print]17(1):
    Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity.
    Diego Gilioli, Simona Fusco, Teresa Tavella, Tatiana Volpari, Antonella Santoro, Martin Schönlein, Kety Giannetti, Edoardo Carsana, Nicolò Gualandi, Roberta Noberini, Chiara Brombin, Salvatore Russo, Sara Feola, Yvonne Giannoula, Rui M M Branca, Janne Lehtiö, Tiina M Sikanen, Markus Haapala, Laura Passerini, Angela Andrisani, Giacomo Farina, Alessia Zangari, Anastasia Conti, Lucrezia Della Volpe, Matteo Barcella, Stefano Beretta, Federico Mario Aletti, Matteo Giovanni Carrabba, Silvia Gregori, Chiara Bonini, Ivan Merelli, Fabio Ciceri, Vincenzo Cerullo, Tiziana Bonaldi, Luca Vago, Clemens A Schmitt, Raffaella Di Micco.
      Chemotherapy resistance and disease relapse are major determinants of treatment failure in acute myeloid leukemia (AML). Therapy-induced senescence (TIS) is one outcome of chemotherapy, but its immunological consequences in AML remain unclear. Here we show that ex vivo chemotherapy induces senescence in a subset of therapy-naïve AML samples. TIS is marked by elevated interferon signaling, upregulation of human leukocyte antigen (HLA) class I and II molecules, and increased presentation of leukemia- and senescence-associated peptides, conferring AML cells antigen-presenting cell-like features. These changes enhance autologous CD4+ and CD8+ T cell responses against AML, both ex vivo and in patient-derived xenograft models. TIS also restores AML sensitivity to immune checkpoint blockade therapy. Mechanistically, we identify reduced Polycomb Repressive Complex 2 (PRC2) activity as central to TIS induction and its immunogenicity. PRC2 inhibition reactivates senescence-related genes and HLA expression in non-senescent AML cells, enabling T cell activation. These findings uncover a senescence-driven immune mechanism with potential to improve therapy outcomes in AML.
    DOI:  https://doi.org/10.1038/s41467-026-76853-1
  15. Blood Cancer Discov. 2026 Sep 02.
    Therapy-persistent leukemia is selectively vulnerable to SLC23A1 restoration via targeting KHSRP.
    Qingyu Luo, Karley S Whalen, Xiaowei Wu, Amanda L Fortune, Jacqueline S Garcia, Kate Marinchev, Lin Zhang, Weiye Qian, Evangeline G Raulston, Yabing Nan, Christopher A G Booth, Kezhi Yan, David E Root, John G Doench, Andrew A Lane.
      Acute myeloid leukemia (AML) is prone to relapse driven by therapy-persistent residual cells. To discover specific vulnerabilities in this population, we performed genome-wide CRISPR interference screens in leukemia cells treated with multiple agents. KHSRP was the top hit, whose depletion sensitized AML cells to therapy and substantially prolonged survival in treated AML-bearing mice. Analysis of in vivo residual disease after venetoclax/azacitidine treatment identified downregulation of the vitamin C and uric acid transporter SLC23A1, which mediated resistance to multiple therapies. KHSRP depletion restored SLC23A1 expression by preventing its ZC3H4-mediated nuclear mRNA degradation. KHSRP depletion therefore enhanced the synergistic cytotoxicity of vitamin C and uric acid, particularly in therapy-persistent leukemia cells. Re-expression of TET2 overrode the chemosensitizing effect of KHSRP depletion in TET2-mutant leukemia, suggesting that KHSRP-linked phenotypes were related to vitamin C and uric acid-mediated TET activation. These findings nominate targeting KHSRP to enhance treatment efficacy and selectively eradicate residual AML.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-26-0030
  16. Haematologica. 2026 Sep 03.
    FLT3-directed therapy in acute myeloid leukemia: lessons from the final analysis of LACEWING.
    Jennifer Marvin-Peek, Courtney D DiNardo.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.301819
  17. Am J Hematol. 2026 Aug 31.
    Real-World Outcomes of Midostaurin Plus Intensive Chemotherapy in FLT3-Mutated AML: The PETHRATIFY Study.
    Mónica Alejandra Romero Riquelme, Gaspar Aspas Requena, Pilar Lloret-Madrid, Cristina Gil, Eliana Aguiar, Mar Tormo, Teresa Del Bernal Del Castillo, Eduardo Rodríguez Arbolí, Josefina Serrano, Joaquín Sánchez-García, Carlos Rodríguez-Medina, José Mário Mariz, Rosa Ayala, Joaquín Martínez-López, María Luz Amigo, Susana Vives, Lorenzo Algarra Algarra, Raimundo García Boyero, Joana Brioso, Tamara Castaño, Juan M Bergua Burgués, Olga Salamero, María Francisca Bass Maturana, Mercedes Colorado, María García Fortes, María José Sayas Lloris, Belén Vidriales Vicente, Carmen Chillón, Esther Pérez Santaolalla, María Dolores Madrigal, Jorge Labrador Gómez, María José García Pérez, Soledad Casado Calderón, Manuel Pérez Encinas, Amaia Balerdi Malcorra, María Solé Rodríguez, Lara María Gómez García, Pilar Herrera Puente, Olga Arce Fernández, Manuel Barrios García, Víctor Noriega, Rosa Fernández, Mamen Mateos, Carolina Lacalzada, Ágata Almela Gallego, María Carmen García Garay, Carmen Couto, José Antonio Pérez-Simón, Eva Barragán González, Pau Montesinos.
      Mutations in FLT3 are present in approximately 30% of patients with AML. The addition of midostaurin (MIDO) to intensive chemotherapy (IC) became standard of care following the RATIFY trial, but comprehensive real-world data spanning the full adult age spectrum and including both FLT3-ITD and FLT3-TKD mutations remain limited. We retrospectively analyzed 1658 adults aged 14-85 years with newly diagnosed FLT3-mutated AML from 129 PETHEMA registry centers: 469 received IC + MIDO and 1189 IC alone. Composite complete remission was higher with IC + MIDO than IC (81.4% vs. 71.7%; p < 0.001) and Day 30 mortality was substantially lower (2.1% vs. 7.1%; p < 0.001). Median overall survival was 47.2 versus 19.3 months (HR 0.64; 95% CI, 0.53-0.76; p < 0.001), and the benefit was sustained after multivariable adjustment (HR 0.73; p = 0.017). In 261 propensity score-matched pairs, the effect was attenuated, remaining significant for event-free survival (HR 0.77; p = 0.029) and showing a nonsignificant trend for OS (HR 0.77; p = 0.06). Allogeneic hematopoietic stem cell transplantation in first remission was more frequent in the IC + MIDO cohort (48.9% vs. 41.3%; p = 0.023). Time-dependent analyses showed the largest MIDO effect among autologous and non-transplanted patients (OS HR 0.45; p = 0.138, and HR 0.69; p = 0.014, respectively). The benefit of MIDO was consistent irrespective of FLT3 mutation type, FLT3-ITD allelic burden, cytogenetic risk, and gender, while less improvement occurred among NPM1 wild type and secondary AML patients. This large real-world cohort confirms the survival benefit of MIDO plus IC across the full adult age spectrum, supporting its standard-of-care status in FLT3-mutated AML.
    Keywords:  FLT3‐mutated; acute myeloid leukemia; front‐line; midostaurin; real‐world
    DOI:  https://doi.org/10.1002/ajh.70488
  18. Oncogene. 2026 Sep 04.
    A step-wise, deterministic and fatal mouse model of myeloid neoplasm with spontaneous acquisition of patient-relevant RTK-RAS mutations.
    Marija A Zarocsinceva, Moosa Qureshi, Nicola K Wilson, George Giotopoulos, Blaise Musabe, Katherine H M Sturgess, M S Vijayabaskar, Sarah J Kinston, Ryan Asby, David J Adams, Brian J P Huntly, Fernando J Calero-Nieto, Berthold Göttgens.
      Leukaemia arises through the stepwise transformation of healthy haematopoietic cells, yet the asymptomatic premalignant phase and its progression to overt disease remain poorly understood. To model this process, we engineered a patient-derived CEBPA mutation into Hoxb8-FL multipotent murine progenitors and transplanted them into syngeneic mice, capturing a clinically silent premalignant stage. All recipients developed overt disease after ~12 months with 100% penetrance and all acquired secondary RTK-RAS mutations, often with identical amino acid changes to those in patients. Single-cell transcriptomics and phenotypic profiling showed that premalignant mutant cells adopt a plasmacytoid dendritic progenitor-like state in vitro which generates both myeloid and B-lymphoid lineages during premalignancy in vivo, with individual tumours restricted to one lineage. The specificity for RTK-RAS mutations coupled with ongoing differentiation, reflects clinically relevant biological contexts thus providing a tractable model of myeloid neoplasm for mechanistic studies and drug discovery.
    DOI:  https://doi.org/10.1038/s41388-026-03964-w
  19. Blood Cancer Discov. 2026 Sep 03.
    Germline noncoding risk variants influence clonal hematopoiesis through altered hematopoietic enhancer activity.
    Trieu Nguyen, Jessica Jeejan, Takeshi Iwasaki, Susan Kales, Joyeeta Chakraborty, Chie Yanase, Aruna Shekhar, Dominika Kwasniak, Aditi Hegde, Richard Voit, Joshua Weinstock, Kristy R Stengel, Keisuke Ito, Ryan Tewhey, Satish K Nandakumar.
      Clonal hematopoiesis of indeterminate potential (CHIP) is a precursor condition characterized by the expansion of mutant hematopoietic stem and progenitor cell (HSPC) clones that increases the risk of hematologic malignancies. Although genome-wide association studies have identified multiple non-coding loci associated with CHIP susceptibility, their mechanisms remain unclear. We hypothesized that CHIP risk variants alter enhancer activity in HSPCs. To test this, we screened 1,374 non-coding variants from 51 CHIP-associated loci using a Massively Parallel Reporter Assay (MPRA) in the CD34+ fraction of MUTZ-3 cells. We identified 87 regulatory variants across 32 loci. Targeted genome editing in hematopoietic cells and complementary reporter assays in primary human HSPCs validated enhancer activity for variants regulating NKD2, FLT3, and MSI2. Functional studies demonstrated that increased MSI2 expression, modeling the effect of the CHIP risk allele, promotes clonal expansion of TET2-deficient HSPCs, providing a mechanistic link between inherited non-coding variation and CHIP clonal expansion.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-26-0046
  20. Exp Mol Med. 2026 Sep 03.
    Bone marrow stromal cells promote chemoresistance in acute myeloid leukaemia through P2RX7-mediated antioxidant defence.
    Ruolan You, Xiaoting Wang, Xiaoming Zheng, Wenqi Fang, Cen Jiang, Jingru Liu, Xiaolin Xu, Maoqing Tan, Danni Cai, Diyu Hou, Jing Zheng, Xinjian Lin, Huifang Huang.
      Acute myeloid leukaemia (AML) remains a therapeutically challenging malignancy owing to its high relapse rates and chemoresistance, often linked to elevated antioxidant defences. Here, we demonstrate that bone marrow stromal cells (BMSCs) confer chemoresistance in AML by upregulating the purinergic receptor P2RX7. Blocking P2RX7 restored chemosensitivity of AML cells. Mechanistically, BMSC-mediated P2RX7 overexpression induces calcium influx and mitochondrial calcium overload, triggering mitochondrial stress and a compensatory antioxidant response. This process involves mitochondrial phosphoglycerate mutase 5 (PGAM5) transducing reactive oxygen species signals, interfering with Keap1-Nrf2 complex formation and leading to Nrf2 stabilization, thereby enhancing cellular antioxidant defences. These findings identify a vital role of P2RX7 in the BMSC-driven redox adaptation programme that underlies AML chemoresistance and highlight P2RX7 signalling as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s12276-026-01839-4
  21. Haematologica. 2026 Sep 03.
    Gilteritinib plus azacitidine in patients with newly diagnosed FLT3 mutation-positive acute myeloid leukemia who were ineligible for intensive chemotherapy: final results of the phase III LACEWING study.
    Eunice S Wang, Pau Montesinos, Mark D Minden, Hassan Sibai, Je-Hwan Lee, Michael Heuser, Tomoki Naoe, Wen-Chien Chou, Kamel Laribi, Jordi Esteve, Jessica K Altman, Violaine Havelange, Anne-Marie Watson, Monica Fumagalli, Elzbieta Patkowska, Jason E Hill, Stanley C Gill, Bhavik J Pandya, Caroline Chen, Nahla Hasabou.
      The phase 3, open-label LACEWING study evaluated efficacy and safety of the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (GIL) plus azacitidine (AZA) in newly diagnosed (ND) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive induction chemotherapy (IIC). Patients were enrolled into a safety cohort (n=15) or randomized (n=168) to GIL+AZA, GIL, or AZA. We present final (6.5-year) outcomes and additional data on mutational subgroups, measurable residual disease (MRD), and pharmacokinetics. Median overall survival (OS) was 9.82 versus 9.23 months (GIL+AZA vs AZA, p=0.182) and 5.24 months (GIL). Corresponding two-year OS rates were 18.8%, 12.9%, and 4.5%. Overall response rates were 70.2% versus 36.8% (GIL+AZA vs AZA, nominal p.
    DOI:  https://doi.org/10.3324/haematol.2026.301112
  22. Blood Adv. 2026 Sep 04. pii: bloodadvances.2026019895. [Epub ahead of print]
    Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.
    Hyunjoo Choi, Sang-Eun Jung, Yesenia Earth, Hyojung Paik, Shuyang Lin, Jiye Yi, Maggie J Cox, Stephen M Sykes, Stephen T Oh, Yoon-A Kang.
      Unfolded protein response (UPR) promotes protein homeostasis under endoplasmic reticulum stress. UPR signaling has numerous functions in metabolism, cancer, immunology, and neurodegenerative diseases. Recent studies also showed that UPR signaling has important roles in hematopoietic stem and progenitor cell biology. However, whether UPR signaling regulates hematopoietic lineage fate decision remains elusive. Here, we found that FcgR- MPP3 generates erythroid lineage and Jak2V617F mutation leads to overproduction of erythroid cells by expanding FcgR- MPP3. We showed that UPR signaling increases myeloid cell production through promoting FcgR- MPP3 transition to granulocyte/macrophage progenitor producing FcgR+ MPP3 at the expense of erythroid lineage via the XBP1 pathway. Under a disease condition, UPR signaling cooperates with Jak2V617F mutation and exacerbates disease phenotype in a mouse model of polycythemia vera (PV) through the ATF4 pathway. Activation of UPR signaling also increased myeloid output in healthy donor bone marrow MPP cells while skewing the output towards erythroid lineage in PV patient bone marrow MPP cells. Together, our results identify a novel function of UPR signaling in hematopoietic lineage specification and provide critical insights into targeting UPR signaling in hematological malignancies.
    DOI:  https://doi.org/10.1182/bloodadvances.2026019895
  23. Leukemia. 2026 Sep 02.
    KLF4/MLL3 complex axis drives NRBP2 transcription to eliminate acute myeloid leukemia cells.
    Meng Yang, Ting Lu, Yicheng He, Cong Chen, Yifei Wang, Guohuan Sun, Yawei Zheng, Jiaxin Qin, Jiali Ye, Xiaowei Xie, Xiangnan Zhao, Honglin Duan, Biao Zhang, Yapu Li, Fang Dong, Chang Xu, Tao Cheng, Hui Cheng, Shangda Yang.
      Acute myeloid leukemia (AML) is a heterogeneous malignancy rooted in hematopoietic stem cell dysregulation. Here, we identify the transcription factor Krüppel-like factor 4 (KLF4) as a potent suppressor of AML growth, with KLF4 overexpression markedly impairing AML cell proliferation. Mechanistically, KLF4 interacts with the lysine methyltransferase 2 C (MLL3/KMT2C) histone methyltransferase complex to activate transcription of nuclear receptor-binding protein 2 (NRBP2), a pseudokinase. Furthermore, integrated transcriptomic and functional analyses identify TNIK (TRAF2- and NCK-interacting kinase) as a pro-leukemic downstream effector restrained by the KLF4-NRBP2 axis. Pharmacological inhibition of TNIK with TNIK-IN-1 inhibits AML cell growth while exerting limited effects on normal hematopoietic cells. Together, these findings establish a KLF4/MLL3 complex-NRBP2 regulatory axis that restrains AML growth through suppression of TNIK expression and provide a rationale for further preclinical evaluation of TNIK inhibition as a therapeutic strategy in AML. Schematic model illustrating the mechanism by which the KLF4/MLL3 complex/NRBP2 axis regulates the progression of AML. In AML cells with basal KLF4 expression, higher expression of TNIK promotes the proliferation of AML cells (upper). Upon KLF4 overexpression, the TRD and ZnF domains of KLF4 bind to MLL3, which facilitates the recruitment of the MLL3 complex to the NRBP2 cis-regulatory regions. This activates NRBP2 transcription and subsequently downregulates TNIK expression, leading to the suppression of AML cell proliferation. Pharmacological inhibition of TNIK by TNIK-IN-1 reduces TNIK protein levels, represses AML cell growth, and induces cell apoptosis (lower). This study reveals a molecular mechanism by which KLF4 governs AML progression, providing a novel therapeutic target and a potential small-molecule inhibitor for AML treatment (Created in BioRender. he, Y. (2026) https://BioRender.com/q0q3j3q ).
    DOI:  https://doi.org/10.1038/s41375-026-03117-8
  24. Br J Haematol. 2026 Sep 02.
    Treatment-free remission in CML patients with prior TKI failure is not influenced by previous BCR::ABL1 kinase domain mutations.
    Simone Claudiani, Silvia Metelli, Myrto Katraki, Fiona Fernando, Andrew J Innes, Chloe Hayden, Dragana Milojkovic.
      
    Keywords:  CML; KD mutations; TFR; TKI failure
    DOI:  https://doi.org/10.1111/bjh.70794
  25. N Engl J Med. 2026 Sep 03. 395(9): 845-858
    Azacitidine-Venetoclax or Induction Chemotherapy for Acute Myeloid Leukemia.
    Amir T Fathi, Alexander E Perl, Geoffrey G Fell, Brian A Jonas, Brittany K Ragon, Alice S Mims, Uma Borate, Gabriel N Mannis, Karen Quillen, Maximilian Stahl, Brandon J Aubrey, Paul Koller, Andrew S Artz, Monzr M Al Malki, Anthony S Stein, Guido Marcucci, Mary Linton B Peters, Timothy A Graubert, Peter Westervelt, Philip C Amrein, Hanno R Hock, Andrew M Brunner, Gabriela Hobbs, Rupa Narayan, Michelle H Lee, Peter G Miller, Alyssa L Watson, Richard Hao, Abigail C Marola, Jennifer Lombardi-Story, Shilton Dhaver, Michael R Grunwald, Yi-Bin Chen, Matthew J Weinstock, Andrew H Matthews, Ian McGovern, Brent L Wood, Christopher S Hourigan, Donna S Neuberg, Areej El-Jawahri, Ibrahim Aldoss.
       BACKGROUND: Induction chemotherapy has long been a key component of curative therapy for fit patients with acute myeloid leukemia (AML), despite its frequently severe side effects and substantial health care utilization. For patients who are ineligible for induction chemotherapy, hypomethylating therapy plus venetoclax is the standard treatment owing to its efficacy and side-effect profile.
    METHODS: In this multicenter, phase 2 trial, we randomly assigned, in a 1:1 ratio, previously untreated adults with AML who were eligible for induction chemotherapy to receive either azacitidine plus venetoclax or induction chemotherapy. Patients with core binding factor fusions, mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3), or mutations in the gene encoding nucleophosmin-1 (NPM1; unless the patient was ≥60 years of age) were excluded. The primary end point was event-free survival.
    RESULTS: A total of 172 patients underwent randomization, with 86 patients assigned to each group. The median age of the patients was 64 years. A total of 72% of the patients had adverse-risk disease according to the European LeukemiaNet 2022 classification. At a median follow-up of 21.9 months, the median event-free survival was 14.5 months (95% confidence interval [CI], 10.4 to 24.4) in the azacitidine-venetoclax group, as compared with 6.2 months (95% CI, 4.1 to 10.1) in the induction chemotherapy group, corresponding to a hazard ratio for event or death of 0.57 (95% CI, 0.39 to 0.84; P = 0.002 by the stratified log-rank test). Infection of grade 3 or higher occurred in 28% of the patients (95% CI, 19 to 39) receiving azacitidine-venetoclax and in 41% of those (95% CI, 30 to 52) receiving induction chemotherapy; hemorrhage of grade 3 or higher occurred in 2% (95% CI, 0.3 to 8) and 12% (95% CI, 6 to 20), respectively.
    CONCLUSIONS: In this phase 2, randomized trial, azacitidine-venetoclax therapy led to significantly longer event-free survival than induction chemotherapy among induction-eligible patients with AML. (Funded by AbbVie and others; PARADIGM ClinicalTrials.gov number, NCT04801797.).
    DOI:  https://doi.org/10.1056/NEJMoa2602804
  26. Blood Neoplasia. 2026 Nov;3(4): 100270
    Timing of response in patients with relapsed/refractory FLT3 mut+ acute myeloid leukemia treated with gilteritinib.
    Alexander E Perl, Mark J Levis, Andrew H Wei, Hee-Je Kim, June-Won Cheong, Jian Li, Sergey Bondarenko, Hisayuki Yokoyama, Naoko Hosono, Nahla Hasabou, Dina Elsouda, Juan Ariza, Jamie Jung-Hee An, Jianxiang Wang.
      This post hoc pooled analysis of ADMIRAL and COMMODORE trials aimed to determine if response kinetics differ for gilteritinib monotherapy in relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML). In total, 205 patients achieved composite complete remission (CRc). This analysis only included the 166 patients (81.0%) who achieved CRc before on-study hematopoietic stem cell transplantation (HSCT). Of these, 148 patients (89.2%) achieved CRc within 6 gilteritinib cycles, 60 patients (36.1%) after cycle 2, and 119 patients (71.7%) after cycle 4. We defined early responders (ERs; n = 60) and later responders (LRs; n = 106) as those who achieved CRc within 2 cycles and after cycle 3, respectively. Multivariate logistic regression analysis indicated that female patients and patients with nucleophosmin 1 comutations were more likely to be ERs than LRs. Median CRc duration was 2.7 months (range, 0-66) for ERs and 3.5 months (range, 0-61) for LRs. More LRs (41 of 106 patients [38.7%]) had best response of CR vs ERs (13 of 60 patients [21.7%]). Median overall survival indexed at CRc date was 9 months for ERs and 10 months for LRs. In ERs and LRs, 14 of 60 patients (23.3%) and 20 of 106 patients (18.9%) underwent HSCT respectively. The rate of drug-related grade ≥3 adverse events was 11.4 events per patient-years in ERs and 7.8 events per patient-years in LRs. Patients with R/R FLT3-mutated AML should continue gilteritinib monotherapy, if tolerated, for a minimum of 6 cycles because later responses can occur. These trials were registered at www.clinicaltrials.gov as NCT02421939 (ADMIRAL) and NCT03182244 (COMMODORE).
    DOI:  https://doi.org/10.1016/j.bneo.2026.100270
  27. Mol Biomed. 2026 Sep 04. pii: 161. [Epub ahead of print]7(1):
    The type I FLT3 inhibitor XL999 overrides secondary FLT3-ITD mutations that arise under gilteritinib and quizartinib treatment in acute myeloid leukemia.
    Shiyang Wang, Yvyin Zhang, Zhiwei Zhong, Jiajun He, Jiaqi Fan, Qi Xiang, Fangfang Yang, Yuping Zhang, Shunqing Wang, Peihong Wang.
      FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD) is a well-characterized genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although FLT3 inhibitors, such as gilteritinib and quizartinib, initially show clinical efficacy, resistance frequently emerges because of secondary mutations. Through a kinase inhibitor library screen, we identified XL999, which exhibits potent antileukemic activity across diverse FLT3-mutant AML cell lines and primary patient samples. Mechanistically, biochemical and molecular docking analyses revealed that XL999 directly binds to FLT3-ITD, potentially independent of the common F691 resistance site, thereby suppressing downstream signaling pathways to induce cell cycle arrest and apoptosis. In preclinical mouse models harboring refractory FLT3-ITD-D835Y or ITD-F691L mutations, oral administration of XL999 effectively reduced the leukemic burden across the peripheral blood, spleen, and bone marrow, significantly prolonging survival compared with gilteritinib and quizartinib, with no overt systemic toxicity observed in short-term mouse tolerability studies. Furthermore, XL999 demonstrated robust efficacy in patient-derived xenograft models, complemented by a favorable oral bioavailability profile. Together, these findings suggest that XL999 may represent an orally bioavailable FLT3 inhibitor with the potential to overcome clinically relevant secondary resistance mutations in FLT3-ITD-positive AML, supporting its further investigation as a therapeutic candidate.
    Keywords:  Acute myeloid leukemia; FLT3 resistance mutation; FLT3-ITD; Gilteritinib; Quizartinib; XL999
    DOI:  https://doi.org/10.1186/s43556-026-00561-x
  28. Br J Haematol. 2026 Sep 02.
    Leveraging venetoclax-induced autophagy to enhance AUTAC-mediated Mcl1 degradation and overcome resistance in acute myeloid leukaemia.
    Ahmed M Elshazly, Nayyerehalsadat Hosseini, Janakiram R Vangala, Xiaoyan Hu, Steven Grant, Senthil K Radhakrishnan.
      
    Keywords:  AUTAC; Bcl2; Mcl1; acute myeloid leukaemia; autophagy; resistance; venetoclax
    DOI:  https://doi.org/10.1111/bjh.70813
  29. Leukemia. 2026 Aug 31.
    Association of sarcopenia with treatment tolerance in older adults with acute myeloid leukemia using artificial intelligence computed tomography-segmentation and a geriatric assessment.
    Samuel J Yates, Elizabeth Terman, Lauren Miller, John F Cursio, Claire Wild, Megan Huisingh-Scheetz, Michael Zhang, Nicholas Feinberg, Karteek Popuri, Mirza Faisal Beg, Varun Akella, Hamed Youshanlouei, Afsheen Noorani, Jamie Mathews, Caner Saygin, Anand A Patel, Olatoyosi Odenike, Richard A Larson, Mariam T Nawas, Wendy Stock.
      
    DOI:  https://doi.org/10.1038/s41375-026-03099-7
  30. Hemasphere. 2026 Sep;10(9): e70460
    Allele burden expansion in JAK2 V617F and CALR-mutated myeloproliferative neoplasms predicts disease progression and is associated with anagrelide treatment.
    Zi Yun Ng, Laurane Cottin, Marine Demoy, Damien Luque Paz, Corentin Orvain, Wayne-Corentin Lambert, Jean-Christophe Ianotto, Eric Lippert, David M Ross, Diana Iarossi, Alesia Khan, Daniel Lock, Catherine Truong, Kamel Laribi, Yun Fan Yang, Laura Li Gagnon, Valerie Ugo, Claire N Harrison, Jennifer O'Sullivan.
      
    DOI:  https://doi.org/10.1002/hem3.70460
  31. Blood Adv. 2026 Sep 01. pii: bloodadvances.2026019689. [Epub ahead of print]
    Infection risk in myelodysplastic syndromes is dynamic and immune driven.
    Alyssa Pradhan, Rakchha Chhetri, Philip Selby, Aidan Sapio, Michelle Maritz, Carla Toop, Chung Hoow Kok, Monika M Kutyna, Anoop K Enjeti, Nirmal Robinson, Emmanuel Gnanamanickam, Morgyn Sylvia Warner, Renjy Nelson, Devendra K Hiwase.
      Infection is a major cause of morbidity and mortality in myelodysplastic syndromes (MDS), yet infection risk remains incompletely defined in the contemporary treatment era. We conducted a retrospective study of 708 patients with MDS to characterize the incidence, microbiology, temporal dynamics, and predictors of infection-related hospitalization over two decades. Overall, 78.8% (n=558) of patients required hospitalization, of which 69.9% were infection related. Infection-related hospitalization was independently associated with inferior overall survival. In multivariable Cox proportional hazards model, comorbidity burden, red blood cell transfusion dependence, higher IPSS-R risk, exposure to chemotherapy or stem cell transplantation, and severe neutropenia independently predicted infection. Among azacitidine-treated patients, 71.4% experienced infection-related hospitalization, with nearly three-quarters occurring within the first six cycles, identifying a critical early vulnerability window. Neutropenia remained the dominant driver of infection risk; however, immune dysfunction independently increased susceptibility. Low monocyte counts, cytokine dysregulation, and TP53 mutations identified high-risk patients despite preserved neutrophil counts, reflecting impaired myeloid reserve. Consistent with this dynamic vulnerability, recent infection or severe neutropenia (<0.5×10⁹/L) increased subsequent infection risk by 2.47-fold. We observed a concerning shift in antimicrobial resistance, with 14% of Gram-negative infections producing extended-spectrum beta-lactamases, 21% of Pseudomonas aeruginosa isolates resistant to piperacillin-tazobactam, and vancomycin-resistant enterococci prevalence increasing from 14% to 46%. Together, these findings identify infection in MDS as a dynamic, prognostically important complication driven by cytopenia, treatment, and immune dysfunction. This supports time-adapted risk stratification, targeted prevention, and antimicrobial stewardship, particularly during early treatment and high-risk disease phase.
    DOI:  https://doi.org/10.1182/bloodadvances.2026019689
  32. Br J Haematol. 2026 Sep 02.
    Development and validation of a machine learning model based on routine laboratory tests for predicting FLT3-ITD mutations in acute myeloid leukaemia.
    Junjun Song, Zhichao Gu, Jin Han, Yuqing Zhang, Lingling Zhao, Han Yan, Jing Lu, Yang Shen, Yongmei Zhu.
      Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are clinically important in acute myeloid leukaemia (AML). We developed and validated a machine learning model using routine laboratory tests to estimate the probability of FLT3-ITD mutations in newly diagnosed AML to prioritise rapid molecular testing. Consecutive patients treated at Ruijin Hospital during 2021-2024 were included. Those diagnosed in 2021-2023 comprised the training cohort, and those in 2024 formed the internal temporal validation cohort, and the BeatAML2 cohort served as external validation. Following Boruta feature selection, seven machine learning algorithms were evaluated via area under the receiver operating characteristic curve (AUC). The optimal model was interpreted using SHapley Additive exPlanations (SHAP) and deployed as a web-based calculator. Overall, 514 patients were included (training, n = 254; validation, n = 84; external validation, n = 176). Boruta algorithm selected five candidate features, and a simple four-feature model was constructed. Gradient boosting machine (GBM) performed best, with AUCs of 0.847, 0.772 and 0.760 in the training, internal validation and external validation cohorts respectively. SHAP analysis showed absolute blast count contributed most to the model. The GBM model may help identify patients with newly diagnosed AML who should be prioritised for rapid molecular testing for FLT3-ITD mutations.
    Keywords:  FLT3‐ITD mutation; acute myeloid leukaemia; machine learning; risk stratification; routine laboratory tests
    DOI:  https://doi.org/10.1111/bjh.70829
  33. Leukemia. 2026 Aug 31.
    Incidence, prevalence, and survival outcomes of patients with myeloproliferative neoplasms in the United States: a Surveillance, Epidemiology, and End Results (SEER) database analysis, years 2000-2021.
    Sachi Singhal, Rahul Mishra, Sankalp Arora, Noha Sharafeldin, Ruchi Desai, Tania Jain, Pankit Vachhani.
      Myeloproliferative Neoplasms (MPNs) are rare hematologic neoplasms. The epidemiology and outcomes of these rare neoplasms warrant an update considering new diagnostic tools and advances in treatment options. NCI's Surveillance, Epidemiology and End Results (SEER)-17 registries were interrogated to analyze adult patients diagnosed with MPN [ICD-O-3 codes: polycythemia vera (PV) 9950/3, essential thrombocythemia (ET) 9962/3, primary myelofibrosis (PMF) 9961/3 and chronic myeloid leukemia (CML) 9875/3] during the years 2000 to 2021. Data of 63,242 (ET, n = 24,172; PV, n = 23,456; PMF, n = 6131; CML, n = 9483) patients were analyzed. The overall incidence rate (IR) for ET, PV, PMF and CML was 1.8, 1.7, 0.5 and 0.7 per 100,000 person-years, respectively. The incidence of ET, PV, and MF increased with age, and the majority of cases were seen after the age of 50. 5-year Relative Survival (RS) for PMF was 50.9% in 2009, to 57.4% in 2013 and 60.6% in 2016. The median overall survival (OS) was 152 months for ET, 150 months for PV, 48 months for PMF, and 202 months for CML. Advancing age was associated with adverse survival across MPN subtypes. Survival of patients with PMF continues to improve over recent years. Important racial and gender variations exist, which were noted in our study.
    DOI:  https://doi.org/10.1038/s41375-026-03124-9
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