bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–07–26
29 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Acute Myeloid Leukemia Subtype-Specific Prognostic Value of NGS in the Setting of Intensive Chemotherapy.
  2. Newly diagnosed acute myeloid leukemia in Fit patients: 2026 treatment algorithms.
  3. Relapse risk and survival benchmarks for non-transplanted acute myeloid leukemia patients in first complete remission.
  4. Molecular and clinical analyses of c-CBL mutations affecting tyrosine 371 in myelodysplastic and proliferative disorders.
  5. Eradication of PPMI clone and improvement in cytopenia using cryopreserved autologous haematopoietic stem cells.
  6. The effect of cohesin mutations on HLA-class II expression in the myeloid leukemia of Down syndrome.
  7. G3BP2 confers venetoclax resistance by stabilizing ELF1-mediated MCL1 transcription in acute myeloid leukemia.
  8. Five-year follow-up of OPTIC: long-term efficacy, safety, and mutation analyses of ponatinib in chronic-phase chronic myeloid leukemia from a randomized phase 2 trial.
  9. JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation.
  10. Eltrombopag Added to Standard Immunosuppressive Treatment as Front-Line Therapy for Severe Aplastic Anemia: Long-Term Outcomes of the Phase-3 Randomized Superiority EBMT-SAAWP RACE Study.
  11. A Phase 1/1b Study of the All-Oral Regimen CC-486 and Venetoclax in Acute Myeloid Leukemia.
  12. LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models.
  13. The NLRC4 Inflammasome Drives Myelodysplastic Syndrome by Linking Epigenetic Reprogramming and Innate Immune Signaling.
  14. Allogeneic hematopoietic cell transplantation from haploidentical donors with total body irradiation versus chemo-based regimens for adult AML patients in first complete remission. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).
  15. The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells.
  16. Real-world outcomes of triplet therapy with gilteritinib, azacitidine and venetoclax in FMS-like tyrosine kinase 3 (FLT3)-mutated relapsed/refractory acute myeloid leukaemia: A UK single-centre experience.
  17. Risk-Adjusted Comparison of Survival in Chronic Myelomonocytic Leukemia With and Without Allogeneic Stem Cell Transplant: Mayo Clinic Experience in 775 Consecutive Patients.
  18. Long-acting pegylated Interferon Gamma (pegIFNG) sensitizes AML cells to killing by donor T cells.
  19. Co-mutation of asxl1 and IDH2R172K enhances leukemogenesis and correlates with epigenetic activation of MAPK and AP-1.
  20. Personalized measurable residual disease assays for acute myeloid leukemia guided by whole-genome sequencing.
  21. Hypomethylating agents-venetoclax as salvage therapy for relapse of AML and MDS after allogeneic HCT.
  22. AAML1831: A Phase III Trial Comparing Standard Induction Therapy With CPX-351 in De Novo Pediatric AML: A Report From the Children's Oncology Group.
  23. Significance of CD34+ Cell Dose on Outcomes of Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation in AML: An Analysis Stratified by MRD Status.
  24. A structure-based modeling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.
  25. Chronic graft vs. host disease following post-transplant cyclophosphamide (PTCy) based prophylaxis vs. non-PTCy prophylaxis.
  26. Editing Around the Target: Epitope Engineering to Protect Stem Cell Grafts.
  27. Ex vivo pretreatment with venetoclax boosts the antileukemic efficacy of therapeutic γδ T cells in AML models.
  28. CCAAT/enhancer-binding protein alpha basic leucine zipper in-frame insertion/deletion (CEBPA bZIP-InDel-inf) defines a favourable-prognosis subgroup in CEBPA-mutated acute myeloid leukaemia.
  29. Cumulative disruption of regulatory genes precedes whole-chromosome gains in acute myeloid leukemia.
  1. Am J Hematol. 2026 Jul 18.
    Acute Myeloid Leukemia Subtype-Specific Prognostic Value of NGS in the Setting of Intensive Chemotherapy.
    Abiola Bolarinwa, Aref Al-Kali, Hassan B Alkhateeb, Abhishek A Mangaonkar, Antoine N Saliba, Mehrdad Hefazi Torghabeh, Aasiya Matin, Michelle A Elliott, Mark R Litzow, William J Hogan, Mithun V Shah, Mrinal M Patnaik, Animesh Pardanani, James M Foran, Talha Badar, Hermant S Murthy, Nathan Punwani, Jeanne M Palmer, Lisa Z Sproat, Dong Chen, Kaaren K Reichard, Rong He, David S Viswanatha, Cinthya J Zepeda-Mendoza, Naseema Gangat, Kebede H Begna, Ayalew Tefferi.
      We examined the prognostic value of routine NGS data in newly diagnosed acute myeloid leukemia (AML) treated with intensive (7 + 3 backbone) induction, specified by AML subtype. A contemporary (2015-2025) series of 545 Mayo Clinic patients (median age 56 years, females 44%) was considered. Median follow-up was 49 months with 341 (63%) allogeneic hematopoietic stem cell transplantations (AHSCT) recorded. AML subtypes included core-binding factor (CBF; N = 72; 13%), primary non-CBF (N = 403; 74%), post-myelodysplastic syndromes (MDS) or post-myelodysplastic/myeloproliferative neoplasms (post-MDS-MDS/MPN; N = 28; 5%), post-MPN (N = 15; 3%), and therapy-related (t-AML; N = 27; 5%). Corresponding complete remission rates, with/without count recovery (CR/CRi), were 89%, 76%, 64%, 27%, and 78% (p < 0.01) and 5-year transplant-censored survival rates 68%, 57%, 21%, 0%, and 55% (p < 0.01). In multivariable analyses, the prognostic value of specific mutations was mostly limited to primary non-CBF AML where adverse karyotype (OR 1.9; p = 0.04) predicted inferior and FLT3-ITD (OR 0.4; p < 0.01) or NPM1MUT/FLT3WT (OR 0.1; p < 0.01) superior CR/CRi while KRASMUT (HR 8.8; p < 0.01), TP53MUT (HR 5.4; p < 0.01), and TET2MUT (HR 2.3; p = 0.01) predicted inferior and NPM1MUT/FLT3WT (HR 0.3; p = 0.01) superior survival. Prognostication in intensively-treated AML should start with subtype specification and recognition of the limited value of NGS in non-primary AML. Post-MPN AML is particularly associated with dismal outcomes and should be prognostically distinguished from post-MDS-MDS/MPN AML. In primary non-CBF AML, in addition to previously established risk factors, the favorable impact of FLT3-ITD on achieving CR/CRi and the unfavorable impact of KRASMUT and TET2MUT on transplant-censored survival were noted and require confirmation from additional studies.
    Keywords:   KRAS ; TET2 ; TP53 ; prognosis; response; survival
    DOI:  https://doi.org/10.1002/ajh.70443
  2. Blood Cancer J. 2026 Jul 18.
    Newly diagnosed acute myeloid leukemia in Fit patients: 2026 treatment algorithms.
    Naseema Gangat, Farhad Ravandi.
      The introduction of venetoclax (a BCL2 inhibitor) and targeted therapies, including inhibitors of CD33, FLT3, IDH1, IDH2, and menin, has expanded treatment options for newly diagnosed acute myeloid leukemia (AML). In younger, fit patients, the primary goal remains long-term survival, which in most cases is secured through allogeneic stem cell transplant. Transplant in first complete remission is recommended for FLT-ITD, TP53 mutated, KMT2A rearranged, AML with other adverse genetic abnormalities, and is considered in most intermediate-risk patients. It is also recommended in relapsed/refractory disease or persistent measurable residual disease (MRD). The role of intensive chemotherapy, such as cytarabine (7) plus anthracycline (3), is limited to patients with core-binding factor AML, NPM1 mutation, CEBPA bZIP mutation and those with intermediate-risk disease. Intensive regimens such as FLAG-IDA and CLIA plus venetoclax have shown impressive long-term outcomes, but their use is not widespread. In FLT3 mutated AML, 7 + 3 plus an FLT3 inhibitor (midostaurin or quizartinib) remains a standard, with venetoclax-hypomethylating agent-FLT3 inhibitor triplets emerging as an alternative. Similarly, in IDH1/2 mutated AML, venetoclax-hypomethylating agent with or without IDH1/2 inhibitor combinations challenge intensive chemotherapy approaches. Patients with TP53 mutations or other adverse-risk features, where intensive chemotherapy is known to be less effective, should be referred for clinical trials. There remains ongoing debate regarding optimal management of fit patients with newly diagnosed AML without targetable mutations, as emerging data suggest that venetoclax- hypomethylating agents may be comparable to intensive chemotherapy in selected patients proceeding to transplant. Accordingly, treatment decisions should be individualized to maximize remission while minimizing toxicity.
    DOI:  https://doi.org/10.1038/s41408-026-01578-9
  3. Haematologica. 2026 Jul 23.
    Relapse risk and survival benchmarks for non-transplanted acute myeloid leukemia patients in first complete remission.
    Eitan Kugler, Farhad Ravandi, Alex Bazinet, Courtney D Dinardo, Naval Daver, Musa Yilmaz, Nicholas J Short, Wei Ying Jen, Jayastu Senapati, Abhishek Maiti, Gautam Borthakur, Guillermo Garcia-Manero, Hagop M Kantarjian, Tapan M Kadia.
      Survival outcomes of patients with acute myeloid leukemia (AML) who achieve complete remission (CR) without allogeneic stem cell transplantation (allo-SCT) remain largely undefined, yet these benchmarks are essential for developing post-remission strategies. We retrospectively analyzed 362 adults with newly diagnosed de novo AML who achieved CR/Incomplete CR (CRi) (between 2016-2023) and did not undergo allo-SCT in first remission. Patients with APL and corebinding factor AML, which are rarely consolidated with allo-SCT, were excluded. The cohort was stratified by low-intensity (LIT, n=257) and intensive therapy (IT, n=105), and survival was evaluated across predefined subgroups. Median relapse-free survival (RFS) and overall survival (OS) were 11 and 19 months, respectively. Venetoclax was associated with significantly lower 24- month relapse rates in both LIT (68% to 45%) and IT (49% to 27%) (p.
    DOI:  https://doi.org/10.3324/haematol.2026.300935
  4. Leukemia. 2026 Jul 22.
    Molecular and clinical analyses of c-CBL mutations affecting tyrosine 371 in myelodysplastic and proliferative disorders.
    Luca Guarnera, Carmelo Gurnari, Zachary Brady, Carlos Bravo-Perez, Matteo D'Addona, Atsushi Marumo, Mark Orland, Praveena Thiagarajan, Serhan Unlu, Christopher Haddad, Aashray Mandala, Eleonora Lumia, Nicole Lelli, Arda Durmaz, Emiliano Fabiani, Maria Teresa Voso, Jaroslaw P Maciejewski, Valeria Visconte.
      
    DOI:  https://doi.org/10.1038/s41375-026-03072-4
  5. Br J Haematol. 2026 Jul 21.
    Eradication of PPMI clone and improvement in cytopenia using cryopreserved autologous haematopoietic stem cells.
    Marissa M Li, Mrinal M Patnaik, Luis F Porrata, Thomas E Witzig.
      
    Keywords:  CH; PPMID; autologous haematopoietic stem cell transplant; clonal haematopoiesis; t‐MN
    DOI:  https://doi.org/10.1111/bjh.70684
  6. Leukemia. 2026 Jul 21.
    The effect of cohesin mutations on HLA-class II expression in the myeloid leukemia of Down syndrome.
    Austin C Boucher, Wojciech Rosikiewicz, Anitria Cotton, Amber L Broadhurst, Te Ling, Rishika Vadlamudi, Melanie Bremm, Anna-Lena Schmell, Lahiri Konada, Madeline Niederkorn, Josiah D Murray, Yichao Li, Shilpa Narina, Sarah Inglott, Anindita Roy, Philip Ancliff, Ricky Tirtakusuma, Jing Ma, Michael P Walsh, Jeffery M Klco, Paul G Thomas, Yiwen Wang, Aristotelis Tsirigos, Yong Cheng, Beisi Xu, Xiaotu Ma, Soheil Meshinchi, Elvin Wagenblast, Shondra M Pruett-Miller, Sridhar Rao, Gang Wu, Yunusa Olufadi, Guolian Kang, Zuzana Tothova, Jeffrey W Taub, Yubin Ge, Paresh Vyas, Jan-Henning Klusmann, John D Crispino.
      Children with Down syndrome (DS) frequently develop transient abnormal myelopoiesis that can evolve to the myeloid leukemia of DS (ML-DS). TAM spontaneously resolves in most cases but progresses to ML-DS with additional mutations, most commonly in the cohesin complex. However, the mechanisms by which these alterations promote leukemia are unknown. We leveraged the RAD21-mutant CMY cell line and RAD21-corrected CMY isogenic clones, as well as patient data, to investigate the effect of cohesin mutations during leukemia progression. RNA-sequencing revealed that HLA-class II genes were significantly down-regulated with cohesin mutations. Furthermore, HLA-DR was found to be lower in ML-DS relative to TAM, and these decreased levels were associated with increased risk of leukemia progression. Multi-omic analyses revealed that haploinsufficiency of RAD21 altered chromatin accessibility and impaired the occupancy of GATA1s and CIITA, the master regulator of HLA-class II gene expression. Chromatin binding of CIITA was increased with RAD21 correction, providing a mechanism by which restoration of cohesin improves HLA-class II expression. Finally, decreased levels of RAD21 or STAG2 expression in other subtypes of AML also exhibited reduced expression of HLA-class II genes. Thus, cohesin may contribute to leukemia by altering HLA-class II gene expression.
    DOI:  https://doi.org/10.1038/s41375-026-03074-2
  7. Leukemia. 2026 Jul 20.
    G3BP2 confers venetoclax resistance by stabilizing ELF1-mediated MCL1 transcription in acute myeloid leukemia.
    Zhixiang Chen, Yuanhua Cai, Yaping Wang, Xiaolin Lai, Xiongbin Yan, Xuechun Wang, Fuquan Tu, Wanting Wu, Huiyin Gao, Yi Zheng, Yingying Zeng, Yang Li, Jinggang Li, Lili Pan, Peiyao Wang, Wei Ji, Lin Xu, Shaoyuan Wang.
      Venetoclax is a promising treatment for acute myeloid leukemia (AML) patients, but resistance occurs following the upregulation of MCL1. The RNA-binding protein G3BP2 is upregulated in various solid tumors, and targeting G3BP2 has been shown to restore chemosensitivity. However, the role of G3BP2 in AML development and venetoclax resistance remains unknown. Herein, an integrated analysis revealed that G3BP2 confers venetoclax resistance and correlates with poor outcomes in AML. G3BP2 deficiency inhibits AML proliferation and induces apoptosis in AML cells and xenograft mice. G3BP2 expression aligns with MCL1 levels across AML cohorts, and the regulatory effect of G3BP2 on MCL1 was validated in AML cells. Notably, G3BP2 and MCL1 do not interact directly; instead, G3BP2 interacts with ELF1 mRNA to increase its stability. The transcription factor ELF1 binds to the MCL1 promoter to induce its expression, which can be attenuated by G3BP2 inhibition. Furthermore, C108-mediated inhibition of G3BP2, in combination with venetoclax, has anticancer effects in primary AML cells and in patient-derived xenografts (PDX). C108 increases the therapeutic efficacy of venetoclax and their combination prolongs overall survival (OS) in AML model mice. These findings identify G3BP2 as a regulator of venetoclax resistance through ELF1-mediated MCL1 transcription, suggesting new therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41375-026-03063-5
  8. Leukemia. 2026 Jul 24.
    Five-year follow-up of OPTIC: long-term efficacy, safety, and mutation analyses of ponatinib in chronic-phase chronic myeloid leukemia from a randomized phase 2 trial.
    Hagop Kantarjian, Michael Deininger, Jane F Apperley, Christopher Kevin Arthur, Charles Chuah, Andreas Hochhaus, Hugues de Lavallade, Jeffrey H Lipton, Elza Lomaia, James McCloskey, Lori Maness, Michael Mauro, Beatriz Moiraghi, Carolina Pavlovsky, Gianantonio Rosti, Philippe Rousselot, Bo Chao, Alexander Vorog, L Evan Reddick, Niti Patel, Meliessa Hennessy, Tammie Yeh, Jorge Cortes.
      The primary analysis of the phase 2 OPTIC trial (NCT02467270) demonstrated optimal benefit:risk with response-based ponatinib dosing (45 mg once daily (QD) reduced to 15 mg QD) upon achieving ≤1% BCR::ABL1IS in patients with tyrosine kinase inhibitor-resistant or T315I-positive chronic-phase chronic myeloid leukemia (CP-CML). Here, we report 5-year long-term outcomes. Overall, 283 patients were randomized to 45-mg, 30-mg, or 15-mg QD starting doses (n = 94, 95, and 94, respectively), with dose reduction to 15 mg QD upon response in the 45-mg and 30-mg cohorts. At data cutoff, 61 patients remained on trial. Median follow-up time was 75-78 months. By 5 years, 60%, 41%, and 40% of patients in the 45-mg, 30-mg, and 15-mg cohorts, respectively, achieved ≤1% BCR::ABL1IS. Five-year progression-free survival rates were 63%, 57%, and 60%, respectively, by cohort; overall survival rates exceeded 80%. In patients with a T315I mutation, 5-year rates of ≤1% BCR::ABL1IS, PFS, and OS were highest in the 45-mg cohort. Exposure-adjusted rates of adjudicated arterial occlusive events were 4.1, 3.8, and 2.0 patients per 100 patient-years, respectively, by cohort; results were comparable in T315I-positive patients. These findings support long-term clinical benefit of response-based ponatinib dosing in third-line CP-CML, especially in patients with the T315I mutation.
    DOI:  https://doi.org/10.1038/s41375-026-03009-x
  9. Blood Adv. 2026 Jul 22. pii: bloodadvances.2025019220. [Epub ahead of print]
    JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation.
    Wentao Han, Hassan Bjeije, Hamza Celik, Michael P Rettig, Nancy Issa, Andrew L Young, Yanan Li, Infencia Xavier Raj, Christine R Zhang, Aishwarya Krishnan, Tyler M Parsons, Samantha Burkart, Jason Arand, Wei Yang, Jeffrey A Magee, Grant Challen.
      Hematopoietic stem cell transplantation is a common treatment for many blood disorders and can be a life-saving therapy for patients with leukemias, lymphomas and multiple myeloma. Umbilical cord blood (UCB) serves as a valuable source of hematopoietic stem and progenitor cells (HSPCs) for transplantation, particularly for patients lacking a matched donor. However, the limited number of repopulating cells in UCB units restricts its clinical utility. Our prior studies showed that genetic deletion of the polycomb repressive complex 2 (PRC2) co-factor Jarid2 in mouse multipotent progenitors (MPPs) conveyed ectopic self-renewal capacity. Here, we hypothesized that the function of human HSPCs could be enhanced through JARID2 inhibition. In this study, we demonstrate that both constitutive and transient knockdown of JARID2 increases the number and enhances the functionality of human HSPCs both in vitro and in vivo. This phenotype was distinct from inhibition of EZH2 in UCB cells, suggesting the mechanism was independent of PRC2 co-factor activity of JARID2. Mechanistically, JARID2 knockdown promotes a quiescent, long-term self-renewal gene expression program governed by STAT1 upregulation and characterized by an MHC class II immunophenotype. Analogous to mice, these mechanisms conferred HSC-like potential to human MPPs in vivo. Taken together, these findings highlight JARID2 inhibition as a novel and reversible approach to expand functional UCB-derived HSPCs ex vivo, potentially improving access to stem cell transplantation for a wider patient population.
    DOI:  https://doi.org/10.1182/bloodadvances.2025019220
  10. Am J Hematol. 2026 Jul 19.
    Eltrombopag Added to Standard Immunosuppressive Treatment as Front-Line Therapy for Severe Aplastic Anemia: Long-Term Outcomes of the Phase-3 Randomized Superiority EBMT-SAAWP RACE Study.
    Severe Aplastic Anaemia Working Party of the EBMT
      The RACE study (NCT02009747) compared horse antithymocyte globulin (hATG) plus cyclosporine A (CsA) ± eltrombopag as initial immunosuppressive treatment (IST) for severe aplastic anemia. Here we report the final 2-year analysis of this prospective randomized phase III study. One hundred ninety-seven treatment-naive patients were randomized to standard IST (hATG 40 mg/kg × 4 days and CsA 5 mg/kg/day; arm A; n = 101) or standard IST + eltrombopag at the dose of 150 mg/day (arm B; n = 96) from day +14 until 6 months (or 3 months, in case of complete response). The median follow-up was 23.2 months. The 2-year cumulative incidence of complete response was significantly superior in arm B (62.4% vs. 35.3%; p < 0.001). The 2-year overall survival (OS) was 86% in arm A and 91% in arm B (p = 0.081), with hazard ratio (HR), adjusted for age and disease severity, of 0.54 (p = 0.064). The 2-year disease-free survival (DFS) was 56% vs. 37% (adjusted HR = 0.49; p < 0.001), while event-free survival (EFS) was 48% vs. 32% (p < 0.001), with adjusted HR = 0.54 (p < 0.001), both significantly superior for arm B. The cumulative incidence of relapse was comparable in the two arms, while evolution to clinical paroxysmal nocturnal hemoglobinuria was 8% in arm A and 1% in arm B (p = 0.041). The risk of clonal evolution remained negligible, with one patient in arm A and two in arm B developing karyotypic abnormalities. The initial hematological response benefit of eltrombopag added to IST as front-line treatment of AA is associated with better 2-year OS, DFS, and EFS without increased risk of secondary myeloid malignancies.
    DOI:  https://doi.org/10.1002/ajh.70445
  11. Blood Adv. 2026 Jul 24. pii: bloodadvances.2026020179. [Epub ahead of print]
    A Phase 1/1b Study of the All-Oral Regimen CC-486 and Venetoclax in Acute Myeloid Leukemia.
    Maria L Amaya, Diana Abbott, Christine M McMahon, Marc S Schwartz, Jonathan A Gutman, Andrew Kent, Mathew G Angelos, Connor Sohalski, Ayele Belachew, Jessica Dell-Martin, Katelyn Anttila, Brett M Stevens, Angelo D'Alessandro, William M Showers, Austin E Gillen, Craig T Jordan, Daniel A Pollyea.
      Venetoclax with azacitidine is the standard of care for newly diagnosed AML patients who are unfit for intensive induction chemotherapy. CC-486 is the oral formulation of azacitidine that is currently approved for post-induction chemotherapy maintenance in AML. In this single center open label, Phase 1/1b study, we investigated CC-486 and venetoclax in relapsed and refractory AML and newly diagnosed patients. In the dose escalation phase, patients received CC-486 at one of two cohorts (200 mg PO days 1-14 and 300 mg PO days 1-14). Venetoclax was given at the 400 mg/day PO regimen, for 28 days, after an initial intra-patient dose escalation per the standard of care. Using a 3+3 study design for these two cohorts, we determined the recommended dose of CC-486 to be 300mg daily on days 1-14. Most common adverse events included nausea, diarrhea, fatigue and cytopenias. The incidence of grade 3 or greater neutropenia or thrombocytopenia was 97% and 66%, respectively. There were no dose limiting toxicities in either cohort. The expansion phase of the study consisted of 10 additional relapsed and refractory patients and 16 patients with newly diagnosed AML. Responses were seen in all phases of the study, and six patients were successfully bridged to hematopoietic stem cell transplant. Correlative analyses including sequencing and metabolomics performed on patient samples suggested this regimen had a similar effect on leukemia stem cells compared with conventional (intravenous) azacitidine and venetoclax. (NCT05287568).
    DOI:  https://doi.org/10.1182/bloodadvances.2026020179
  12. Blood Cancer Discov. 2026 Jul 23.
    LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models.
    Nathan A Brooks, Anna Skwarska, Vivian Salama, Mark H Bender, Lisa Kays, Robin I DeWalt, Bryan Perria, Deepti Thete, Jason R Manro, Rachel Cavitt, Rebecca Leon, Sandra Gomez, Raquel Torres, John M Strelow, Paul Milligan, Kate Newell, Kenneth D Roth, Jean-Emmanuel Sarry, Steven M Chan, Danalyn Manglicmot Lagutan, Richard Romero, Stephen Antonysamy, Robert L Johnson, Xueqian Gong, Renato A Bauer, Timothy P Burkholder, Patric J Hahn, Zoran Rankovic, Serge L Boulet, Courtney D DiNardo, Marina Konopleva, Raymond Gilmour.
      Acute myeloid leukemia (AML) is an aggressive blood disorder characterized by rapid growth of poorly differentiated myeloid cells. Gain-of-function mutations in isocitrate dehydrogenases (IDHs) are detected in ~20% of AML and ~80% of secondary gliomas. Mutant IDH1/2 isoenzymes acquire neomorphic activity to produce 2-hydroxyglutarate (2-HG) oncometabolite, resulting in hypermethylated DNA and histones, altered gene expression, and blocked differentiation of hematopoietic progenitors. Here, we presented preclinical development of LY3410738, an oral, dual IDH1/2 inhibitor with potential to penetrate the blood-brain barrier. LY3410738 covalently inhibited mutated-IDH1/2, reduced 2-HG levels at low nanomolar concentrations in human AML and glioma models, and demonstrated efficacy in AML patient-derived xenografts (PDXs) in vivo, inducing myeloid differentiation. LY3410738 retained in vitro activity in cancer models with acquired secondary IDH1/2 mutations conferring resistance to ivosidenib and enasidenib. LY3410738 synergized and was well tolerated with standard-of-care regimens such as cytarabine, azacitidine, venetoclax, or midostaurin in IDH1/2-mutated AML PDXs.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0379
  13. Blood Adv. 2026 Jul 24. pii: bloodadvances.2026020095. [Epub ahead of print]
    The NLRC4 Inflammasome Drives Myelodysplastic Syndrome by Linking Epigenetic Reprogramming and Innate Immune Signaling.
    Chuan Chen, Fan Liu, Tasleem Arif, Na Man, Francesco Tamiro, Daniel Bilbao, Concepcion Martinez Caja, Krystal Hossack, Narges Rostami, Gloria Mas Martin, Stephanie Duffort, Hidehiro Itonaga, Julio Poveda, Jennifer R Chapman, Stephen D Nimer.
      Myelodysplastic syndromes (MDS), which are hematopoietic stem cell malignancies, are often accompanied by signs of chronic inflammation, that can in turn drive the pathogenetic process. The precise mechanisms dysregulating inflammatory and innate immune signaling in MDS hematopoietic stem and progenitor cells (HSPCs) remain under investigation. We report that mice lacking Tet2 developed a hyper-inflammatory state, which can be further fueled by LPS-induced inflammation. This chronic inflammation temporarily promotes the self-renewal and myeloid differentiation of Tet2-deficient HSPCs; however, it ultimately accelerates HSC exhaustion and triggers MDS development in chimeric mouse models. Driving this phenotype was the activation of the NLRC4 inflammasome pathway. Notably, Nlrc4 depletion in Tet2-deficient mice impaired MDS development and improved the survival of these mice. These findings uncover a novel mechanistic basis for the MDS-associated inflammation and provide new targeting opportunities in its management.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020095
  14. Bone Marrow Transplant. 2026 Jul 20.
    Allogeneic hematopoietic cell transplantation from haploidentical donors with total body irradiation versus chemo-based regimens for adult AML patients in first complete remission. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).
    Enrico Maffini, Myriam Labopin, Anna Maria Raiola, Didier Blaise, Stefania Bramanti, Simona Sica, Yener Koc, Mi Kwon, Maija Itäla-Remes, Massimo Martino, Lucía López Corral, Jiri Pavlu, Benedetto Bruno, Alexandros Spyridonidis, Bipin Savani, Arnon Nagler, Fabio Ciceri, Mohamad Mohty.
      Adults with acute myeloid leukaemia (AML) receiving T-cell replete hematopoietic cell transplantation (HCT) from haploidentical donors are increasing. It is unknown whether a total body irradiation (TBI)-based regimen is associated with better survival than a chemotherapy (chemo)-based regimen. This is a retrospective analysis of AML patients in first complete remission who received a HCT from a haploidentical donor, from 2010 to 2022, reported to the ALWP of the EBMT database. Patients were divided into TBI vs. chemo-based regimens and stratified by transplant conditioning intensity (TCI): low (1-2) vs. intermediate/high (2.5-6). A total of 2309 patients (median age 56.8 years, range 18-82) were included. For patients with low TCI, multivariate analysis confirmed higher disease relapse with TBI (HR 1.49, 95% CI 1.03-2.16, p = 0.033) with respect to chemo, but lower NRM (HR 0.56, 95% CI 0.36-0.89, p = 0.013). In TCI intermediate/high, TBI was associated with a higher risk of NRM (HR 1.71, 95% CI 1.07-2.74, p = 0.026), inferior OS (HR 1.61, 95% CI 1.08-2.42, p = 0.02) and GRFS (HR 1.43, 95% CI 1.03-1.95, p = 0.034). The use of TBI in AML transplanted from haploidentical donors is feasible, although it does not appear to be associated with a survival advantage compared to chemotherapy-only regimens. Prospective clinical trials are warranted.
    DOI:  https://doi.org/10.1038/s41409-026-02988-w
  15. Blood Cancer Discov. 2026 Jul 21.
    The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells.
    Sweta B Patel, Daniel R Moskop, Steven Moreira, Stephanie Gipson, Colin C Anderson, Alexandra Crook, Maxwell McCabe, Daniel Stephenson, Hannah E Terry, Andrew Kent, Tracy N Young, Anna E Krug, Connon I Thomas, Caitlin Price, Monica Ransom, Regan Miller, Ana Vujovic, Mohammad Minhajuddin, Mark J Althoff, The Cuijbp Consortium, Anthony J Saviola, Brett M Stevens, Robert S Welner, Ekaterina L Andrianova, Andrei V Gudkov, Anza Darehshouri, Julie A Reisz, Travis Nemkov, Angelo D'Alessandro, Austin E Gillen, Daniel A Pollyea, Craig T Jordan, Eric M Pietras.
      High-risk myelodysplastic syndrome (HR-MDS) is a malignant clonal disorder originating in hematopoietic stem and progenitor cells (HSPCs). The current standard of care for HR-MDS patients has a poor response, thus necessitating exploration of vulnerabilities of HR-MDS HSPCs for better clinical outcomes. We demonstrate that compared to healthy HSPCs, HR-MDS HSPCs have significant upregulation of metabolic proteins leading to increased oxygen consumption, suggesting an increased metabolic rate. Corroboratively, compared to healthy HSPCs, HR-MDS HSPCs have increased abundance of NADH dehydrogenases, which are crucial for energy production. Therefore, we investigated whether HR-MDS HSPCs are functionally reliant on NAMPT, the rate-limiting enzyme in the nicotinamide salvage pathway of NAD anabolism. NAMPT inhibition reduced the oxygen-consuming capacity of HR-MDS-HSPCs compared to healthy. Importantly, NAMPT inhibition significantly impaired function, increased cell death, and reduced disease burden specifically of HR-MDS HSPCs. Collectively, our data suggests that NAMPT is a promising therapeutic target to eradicate HR-MDS HSPCs.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0498
  16. Br J Haematol. 2026 Jul 19.
    Real-world outcomes of triplet therapy with gilteritinib, azacitidine and venetoclax in FMS-like tyrosine kinase 3 (FLT3)-mutated relapsed/refractory acute myeloid leukaemia: A UK single-centre experience.
    Wei Yee Chan, Hannah Al-Yousuf, Ho Pui Jeff Lam, Sarah Leong, Jiexin Zheng, Richard Burt, Andrew J Wilson, Ke Xu, Kate Stringaris, Samah Alimam, Kavita Raj, Rajeev Gupta, Panagiotis Kottaridis, Anish Tailor, Rebecca Burgoyne, Marc R Mansour, Asim Khwaja, Rob Sellar, Elspeth M Payne, Jenny O'Nions.
      In FMS-like tyrosine kinase 3 (FLT3)-mutated relapsed/refractory acute myeloid leukaemia, gilteritinib, azacitidine and venetoclax is an effective salvage option with an ORR of 100% (mCRc [MLFS + CRc] 93%). Sixty-two per cent of patients treated with intention-to-transplant proceeded to allogeneic haematopoietic stem cell transplant, of whom 50% remain in long-term remission (median follow-up 43 months).
    Keywords:   AML ; FLT3 ; gilteritinib; real‐world; venetoclax
    DOI:  https://doi.org/10.1111/bjh.70676
  17. Am J Hematol. 2026 Jul 24.
    Risk-Adjusted Comparison of Survival in Chronic Myelomonocytic Leukemia With and Without Allogeneic Stem Cell Transplant: Mayo Clinic Experience in 775 Consecutive Patients.
    Ali Alsugair, Saubia Fathima, Mohammad M Alhousani, Estefania Gauto Mariotti, Abiola Bolarinwa, Priyansh Faldu, Muhammad Yousuf, Clifford M Csizmar, James Foran, Abishek A Mangaonkar, Mark Litzow, Hemant Murthy, Lisa Sproat, Jeanne Palmer, Aasiya Matin, Ernesto Ayala, James Slack, Luis Porrata, Madiha Iqbal, Nandita Khera, Nathan Punwani, Saad Kenderian, Saurabh Chhabra, Kebede H Begna, Animesh Pardanani, William J Hogan, Mithun Vinod Shah, Hassan B Alkhateeb, Naseema Gangat, Mrinal Patnaik, Ayalew Tefferi.
      The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST-Mol) differentiate low, intermediate, and high-risk groups. The objective of the current retrospective study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients (n = 775; 68% males, median age 71 years) with CMML, overall and adjusted for baseline BLAST/BLAST-Mol risk categories. At a median follow-up of 77 months, 151 (20%) patients underwent ASCT. Overall survival (OS) was longer in the ASCT compared to the non-ASCT cohorts (median 77 vs. 28 months; p < 0.01). The significant difference in OS between the ASCT and non-ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high-risk (median 50 vs. 14 months; p < 0.01), intermediate-risk (81 vs. 28 months; p < 0.01), and low-risk (111 vs. 65 months; p = 0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST-Mol with respective p values of < 0.01, < 0.01, and 0.08, respectively. Time-dependent cox models confirmed the favorable survival impact of ASCT in the BLAST/BLAST-Mol high- and intermediate-risk groups. The current study highlights the benefit of ASCT for BLAST/BLAST-Mol high- and intermediate-risk groups in CMML and its potential to overcome the adverse impact of some high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.
    Keywords:  BLAST; BLAST‐Mol; CMML; bone marrow transplantation; treatment
    DOI:  https://doi.org/10.1002/ajh.70453
  18. Blood Adv. 2026 Jul 21. pii: bloodadvances.2026019670. [Epub ahead of print]
    Long-acting pegylated Interferon Gamma (pegIFNG) sensitizes AML cells to killing by donor T cells.
    Vaishali Basu, Gregory Mannino, Laura F Mpofu, Heidi Struthers, Sharon J Carlson, George N Cox, David H Spencer, Michael P Rettig, Matt Christopher.
      AML relapse after allogeneic hematopoietic stem cell transplantation (HCT) is associated with loss of MHC class II (MHC-II) expression on AML cells. Although the mechanisms by which this occurs are unknown, the loss of antigen presentation by MHC-II may contribute to AML relapse after transplant. In this study, we performed single cell RNA sequencing on patient samples with MHC-II loss and observed downregulation of inflammatory signaling pathways, including type I and II interferons and TNFα, in MHC-II-low AML cells compared to MHC-II-high AML cells from the same samples. Treatment with exogenous interferon gamma (IFNG) but not IFNA or TNFA restored MHC-II expression in MHC-II-low post-HCT relapse cells, and IFNG treatment of THP1 cells increased alloreactivity of HLA-mismatched donor T cells in vitro. Since recombinant IFNG has a short half-life in vivo, we tested whether a novel, long-acting pegylated IFNG (peg-IFNG) could increase sensitivity of AML cells to donor T cell clearance in mouse models. Peg-IFNG treatment was well-tolerated in healthy mice and led to more robust upregulation of MHC-II expression compared to recombinant IFNG. Additionally, pretreatment with peg-IFNG treatment enhanced AML cell clearance by donor T cells in xenografts, raising the possibility that sensitization of AML cells by exogenous long-acting IFNG may be of therapeutic benefit in AML patients relapsing after HCT.
    DOI:  https://doi.org/10.1182/bloodadvances.2026019670
  19. Blood Adv. 2026 Jul 23. pii: bloodadvances.2026019586. [Epub ahead of print]
    Co-mutation of asxl1 and IDH2R172K enhances leukemogenesis and correlates with epigenetic activation of MAPK and AP-1.
    Fangfang He, Yao Ruan, Lingge Tu, Dandan Wang, Xinyu Miao, Jun Mun Liew, Lichuan Zheng, Chun Fung Sin, Xudong Liu, Yanwen Shao, Kenneth Kin Leung Kwan, Leslie Kar-Fai Chan, Wan Hei Jeffrey Hui, Wan Yu Annie Ho, Sze Pui Tsui, Runsheng Li, Carmen Chak-Lui Chak-Lui Wong, Alvin Chun Hang Ma, Yiyue Zhang, Wenqing Zhang, Anskar Yh Leung, Xuan Sun.
      Co-mutations of asxl1 and IDH2 are associated with aggressive acute myeloid leukemia (AML), yet the underlying mechanisms have remained poorly understood. We generated a zebrafish model combining asxl1 mutation and IDH2R172K mutation that recapitulates the clinicopathologic and molecular features of high-risk AML with differentiation blockade and reduced animal survival. The double mutant exhibited promoter hypermethylation, downregulation of tet2 expression, and showed global changes in methylation profiles. Genes pertaining to MAPK and AP-1 pathway were upregulated, associated with NADPH oxidase (NOX) expression and an increase in reactive oxygen species (ROS). Single-cell RNA-sequencing confirmed differentiation arrest in HSC-progenitor with activation of MAPK and AP-1 signaling. The double mutants showed resistance to the IDH2 inhibitor but were sensitive to ROS or DNA methylation targeting. In silico analysis of gene expression of human AML carrying co-mutation of ASXL1/IDH2 also showed activation of the MAPK and AP-1 pathway. Our findings underscored an epigenetic-metabolic signaling circuit driving leukemogenesis and revealed novel therapeutic strategies for this AML subtype.
    DOI:  https://doi.org/10.1182/bloodadvances.2026019586
  20. Haematologica. 2026 Jul 23.
    Personalized measurable residual disease assays for acute myeloid leukemia guided by whole-genome sequencing.
    Niveditha Ravindra, Rasha W Al-Ali, Justin Lack, Clifton L Dalgard, Eddy VanCollenburg, Adam Corner, Lan Beppu, Harry Erba, Megan Othus, R Coleman Lindsley, Jerald P Radich, Laura W Dillon, Christopher S Hourigan.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300715
  21. Blood Neoplasia. 2026 Aug;3(3): 100257
    Hypomethylating agents-venetoclax as salvage therapy for relapse of AML and MDS after allogeneic HCT.
    Diana T Samuels, Brian J Ball, Ni-Chun Tsai, Salman Otoukesh, Shukaib Arslan, Hoda Pourhassan, Amanda Blackmon, Vaibhav Agrawal, Idoroenyi Amanam, Haris Ali, Amandeep Salhotra, Ibrahim Aldoss, Paul Koller, Ahmed Aribi, Karamjeet Sandhu, Andrew Artz, Eileen Smith, Forrest Stewart, Pamela Becker, Monzr M Al Malki, Anthony Stein, Guido Marcucci, Stephen J Forman, Ryotaro Nakamura, Vinod Pullarkat.
      Relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a challenge for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and salvage therapy in this setting is not standardized. Given the efficacy of hypomethylating agents and venetoclax (HMA-VEN) in the frontline and relapsed settings, we evaluated the use of this therapy for post-alloHCT relapse. Eighty-three patients with AML (n = 69) or MDS (n = 14) who relapsed after alloHCT were included in this retrospective analysis. The median time to relapse after alloHCT was 7.0 months. Most patients (55%) had prior VEN exposure, and 28% of these patients had previously experienced treatment failure with a VEN-based regimen. HMA-VEN treatment-emergent toxicities were predominantly neutropenia and thrombocytopenia; however, the 30-day mortality was only 3.6%. There were 3 deaths within 30 days because of infectious complications. HMA-VEN led to a complete response (CR) or CR with incomplete hematological recovery in 48% of the patients, with 58% of these patients achieving minimal residual disease negativity. In multivariable analysis, European LeukemiaNet 2024 genetic risk stratification was a predictor of survival outcome. Additionally, prior VEN failure was not a predictor of overall survival. In conclusion, HMA-VEN provides an efficacious and well-tolerated option for post-alloHCT AML or MDS relapse regardless of their prior therapy and may allow responders to undergo a second alloHCT with curative intent.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100257
  22. J Clin Oncol. 2026 Jul 24. JCO2502979
    AAML1831: A Phase III Trial Comparing Standard Induction Therapy With CPX-351 in De Novo Pediatric AML: A Report From the Children's Oncology Group.
    Jessica A Pollard, Todd A Alonzo, Robert B Gerbing, Matthew Kutny, Betsy Hirsch, Gordana Raca, Kasey Leger, Jennifer Wilkes, Reena Pabari, Aman Wadhwa, Zachary Graff, Samir Kahwash, Karen Chisholm, Joseph Chewning, John Horan, Richard Aplenc, Andrew Place, Sarah K Tasian, Katherine Tarlock, Sarah Menig, Olga Militano, Bonnie Ky, Chad Hudson, Michael R Loken, Andrew Menssen, Lisa Eidenschink Brodersen, Soheil Meshinchi, Edward Anders Kolb, Todd M Cooper.
       PURPOSE: The Children's Oncology Group phase III clinical trial AAML1831 (ClinicalTrials.gov identifier: NCT04293562) evaluated liposomal daunorubicin and cytarabine (CPX-351) versus standard daunorubicin/cytarabine (DA) induction therapy in children and young adults with newly diagnosed AML. We hypothesized that CPX-351 given during induction 1 and 2 would improve outcomes compared with DA.
    PATIENTS AND METHODS: Patients (21 years and younger) were randomly assigned to two cycles of DA induction (arm A = DA) or CPX-351 (arm B = CPX-351). All patients also received gemtuzumab ozogamicin in induction 1. Postinduction chemotherapy was according to risk assignment made at the end of induction 1 (EOI1). Those with high-risk (HR) AML received consolidation with allogeneic hematopoietic stem-cell transplantation (HSCT), whereas low-risk (LR) patients received chemotherapy alone. Protocol-specified interim analysis monitored efficacy and futility of CPX-351 induction with respect to the primary end point, event-free survival (EFS) from study entry. Disease-free survival (DFS) was calculated to determine the impact of EOI1 risk assignment.
    RESULTS: Seven hundred twenty-one eligible patients with FLT3 wild-type AML were randomly assigned to DA (n = 358) or CPX-351 (n = 363). Interim analysis determined that the futility monitoring rule was crossed because of inferior EFS in the CPX-351 arm and the random assignment was stopped. The two-year EFS from study entry was 62.2% for DA versus 51.2% for CPX-351 (P = .011). DFS for patients with HR AML was comparable for both arms. However, DFS was significantly lower and cumulative incidence of relapse (CIR) was higher for LR patients assigned to CPX-351 versus DA (2-year DFS from EOI1: DA: 73.8% v CPX-351 57.5% [P = .001]; 2-year CIR Arm DA: 23.6% v CPX-351: 39.9% [P = .001]).
    CONCLUSION: CPX-351 was inferior to DA induction in the AAML1831 trial with differential EFS largely driven by events in LR patients.
    DOI:  https://doi.org/10.1200/JCO-25-02979
  23. Transplant Cell Ther. 2026 Jul 21. pii: S2666-6367(26)00578-6. [Epub ahead of print]
    Significance of CD34+ Cell Dose on Outcomes of Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation in AML: An Analysis Stratified by MRD Status.
    Margery Gang, Megan Othus, Anne-Chloe Olix, Gurbani Kaur, Fazal Yakub, Chris Davis, Ryan S Basom, Kate A Markey, Derek L Stirewalt, Laura S Connelly-Smith, Filippo Milano, Roland B Walter.
       BACKGROUND: Reduced toxicities with reduced-intensity and non-myeloablative conditioning (collectively, non-MAC) regimens have expanded access of allogeneic hematopoietic cell transplantation (HCT) to older and less fit adults with acute myeloid leukemia (AML). Relative to myeloablative conditioning (MAC), non-MAC regimens rely more heavily on immunological effects to prevent post-HCT relapse from AML. Whether there is an optimal CD34+ cell dose in this setting remains controversial, and how measurable residual disease (MRD) might impact the interplay between CD34+ cell dose and outcome is unknown.
    OBJECTIVE: To evaluate the association between infused CD34+ cell doses and post-HCT outcomes, including relapse, overall survival, and graft-versus-host disease (GVHD), in adults with AML undergoing non-MAC allografting, using pre-HCT MRD status as a modulating factor.
    STUDY DESIGN: In this retrospective single-center study, we identified 455 adults with AML or MDS/AML in first or second morphologic remission who underwent non-MAC and received mobilized peripheral blood stem cell allografts from 10/10-HLA matched (n=352), HLA mismatched (MMUD; n=80), or HLA-haploidentical (n=23) donors and had available flow cytometric data on infused CD34+ cell doses. Pre-HCT MRD testing by 10-color MFC was available for all patients. Probabilities of relapse, overall survival (OS), and GVHD were analyzed.
    RESULTS: In multivariable analysis of the 10/10-HLA matched cohort, the lowest CD34+ dose tertile (T1) was associated with a significantly higher relapse (HR=2.01 [1.29-3.14], P=0.002), but decreased moderate-to-severe chronic GVHD (HR=0.55 [0.34-0.89], P=0.014) compared to the intermediate dose (T2). In subgroup analyses, the 3-year relapse incidence was significantly higher in low (T1) vs. high (T2-3) CD34+ cell doses in the MRDneg cohort (42% vs. 26%, P=0.018), and was numerically higher, but not statistically different in the MRDpos cohort (60% vs. 48%, P=0.6). However, there was not a significant interaction between MRD status and CD34+ cell dose group (P=0.51). There was no significant impact of low (T1) vs. high (T2-3) CD34+ cell dose on 3-year overall survival (49% vs. 58%, P=0.12), 100-day noon-relapse mortality (3% vs. 4%, P=0.50), 28-day neutrophil (97% vs. 98%, P=0.11) and platelet (92% vs. 95%, P=0.20) engraftment, or 100-day grade 3-4 acute GVHD (8% vs. 8%, P=0.98). In exploratory analysis of the MMUD cohort, although the lowest CD34+ tertile was not associated with relapse (HR=1.12 [0.35-3.53], P=0.85), there was a non-significant trend toward increased relapse risks with higher (T3) versus intermediate (T2) CD34+ doses (HR=2.50 [0.88-7.15], P=0.087). There was no association between CD34+ cell doses and relapse in the HLA haploidentical cohort.
    CONCLUSIONS: In patients with AML undergoing 10/10-HLA matched non-MAC allografting, lower CD34+ cell doses were associated with an increased relapse risk- particularly in the MRDneg cohort- and lower GVHD risk, with no impact on OS. These findings suggest that selection of "optimal" CD34+ cell dose targets may need to be tailored to individual patient's risk of disease relapse versus chronic GVHD. Future studies are needed to better evaluate these findings across alternative HCT platforms (including MMUD and haploidentical cohorts) and to further define the interaction between graft cell composition, pre-HCT disease burden, and conditioning intensity.
    Keywords:  CD34 cell; acute myeloid leukemia; hematopoietic cell transplantation; measurable residual disease; non-myeloablative
    DOI:  https://doi.org/10.1016/j.jtct.2026.07.023
  24. iScience. 2026 Aug 21. 29(8): 116875
    A structure-based modeling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.
    Luke Jones, Oleksii Rukhlenko, Tânia Dias, Hiroaki Imoto, Ciardha Carmody, Kieran Wynne, Boris N Kholodenko, Jonathan Bond.
      Mutations activating RAS/RAF/MEK/ERK signaling confer poor outcomes in acute myeloid leukemia (AML), but targeting this pathway is challenging. We used a structure-based, dynamic RAS pathway model to predict RAF inhibitor (RAFi) combinations that synergistically suppress RAS-mutant AML. In silico models predicted synergy for two iterations of conformation-specific RAFi's which were validated in vitro. Lifirafenib (type II) + encorafenib (type I½) was highly synergistic against NRAS- and KRAS-mutant AML cells, while lifirafenib + SB590885 (type I) synergy was NRAS-mutant-specific. Combination efficacy correlated with measured RAS pathway activity. Leveraging in silico pharmacokinetic predictions, we tested RAFi combinations in an NRAS-mutant AML patient-derived xenograft, finding improved leukemia growth delay and survival compared with single agents. Both combinations showed site-specific efficacy against circulating and spleen-resident blasts. In summary, our integrated modeling approach effectively identified non-obvious RAFi combinations that are effective in vitro and in vivo, thereby suggesting alternative therapeutic strategies for RAS-mutant AML.
    Keywords:  acute myeloid leukemia; drug combination; ras; structure-based modeling
    DOI:  https://doi.org/10.1016/j.isci.2026.116875
  25. Blood Adv. 2026 Jul 21. pii: bloodadvances.2026020655. [Epub ahead of print]
    Chronic graft vs. host disease following post-transplant cyclophosphamide (PTCy) based prophylaxis vs. non-PTCy prophylaxis.
    Joseph A Pidala, Jongphil Kim, Jose Laborde, Samantha Knott, Krishnakar Mogili, Justin Zinn, Alicia Renee Monroe, Rawan Faramand, Reshma Ramlal, Farhad Khimani, Doris K Hansen, Nancy E Torres Luna, Michael D Jain, Lia E Perez, Asmita Mishra, Nima Ghalehsari, Omar Alexis Castaneda-Puglianini, Melissa Alsina, Fabiana Perna, Michael Nieder, Abu-Sayeef Mirza, Hien D Liu, Taiga Nishihori, Alaa Ali, Deepakbabu Chellapandian, Frederick L Locke, Nelli Bejanyan, Claudio Anasetti, Aleksandr Lazaryan.
      Chronic GVHD is less frequent after post-transplant cyclophosphamide (PTCy)-based prophylaxis, but its clinical characteristics and outcomes compared with chronic GVHD following non-PTCy approaches remain understudied. We addressed this through a single-center retrospective study of 1,534 consecutive adult transplants (PTCy: n = 477; non-PTCy: n = 1,057) using matched related or matched/mismatched unrelated donors. The cumulative incidence of NIH moderate/severe chronic GVHD was significantly lower after PTCy (17% v 46%; P < .001). Among chronic GVHD-affected patients (PTCy: n = 163; non-PTCy: n = 656), chronic GVHD after PTCy involved fewer organ sites, had lower severity scores, and less NIH moderate/severe disease overall. However, this profile did not translate into improved survival. Univariate analysis demonstrated higher non-relapse mortality (24-month NRM: 22% v 13%; P = .014) for the PTCy group, while on multivariate analysis NRM was associated with increased age, NIH overall moderate/severe chronic GVHD severity, prior grade III/IV acute GVHD, reduced platelet count and increased bilirubin. Chronic GVHD after PTCy was associated with increased infectious complications despite reduced immunosuppressive (IS) therapy and higher rates of complete IS discontinuation. Overall, PTCy‑based prophylaxis was associated with a lower incidence and severity of chronic GVHD, and after adjustment for established prognostic factors, mortality following chronic GVHD diagnosis was comparable to that observed after non‑PTCy prophylaxis approaches. Multicenter validation of these findings and novel strategies to mitigate non-relapse mortality in chronic GVHD are warranted.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020655
  26. Blood Adv. 2026 Jul 22. pii: bloodadvances.2025018227. [Epub ahead of print]
    Editing Around the Target: Epitope Engineering to Protect Stem Cell Grafts.
    Joanne Baek, Gabriele Casirati, Pietro Genovese, Saar I Gill.
      Targeted immunotherapies have transformed the treatment of hematologic malignancies, yet their clinical utility is often constrained by on-target, off-tumor toxicity arising from shared antigen expression between malignant cells and essential healthy tissues. An early approach to mitigate this limitation involved the knockout (KO) of the target antigen in donor hematopoietic stem and progenitor cells (HSPCs). However, this strategy is restricted to markers that are dispensable for normal hematopoietic function. Epitope engineering has emerged as an alternative paradigm to decouple therapeutic susceptibility from physiological function by modifying the target antigen on healthy cells while preserving biological activity. In this review, we discuss recent advances in base and prime editing approaches used for epitope editing. We examine recent preclinical and emerging translational studies of this strategy in both malignant and non-malignant contexts. Finally, we discuss challenges related to editing efficiency, off-target effects, delivery strategies, and long-term safety in hematopoietic stem cells. Collectively, epitope engineering of hematopoietic stem cells represents a versatile platform to expand the therapeutic window of precision immunotherapies and may enable safer, more effective combinatorial treatment strategies for both non-malignant and malignant hematologic conditions.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018227
  27. J Clin Invest. 2026 Jul 23. pii: e202932. [Epub ahead of print]
    Ex vivo pretreatment with venetoclax boosts the antileukemic efficacy of therapeutic γδ T cells in AML models.
    Xingchi Chen, Lin Zhang, Bingbing Yan, Yinqiang Sui, Weiwei Ma, Hui Zhao, Yining Wang, Kepeng Yang, Jiewen Ma, Baolin Tang, Yonghui Zhang, Xiaoyu Zhu.
      Ex vivo engineering strategies for adoptive αβ T-cell therapies increasingly use pharmacological modulation to improve survival, expansion, and antitumor activity. Short-term exposure to the BCL-2 inhibitor venetoclax during αβ T-cell manufacturing enhances apoptotic priming and effector persistence, suggesting a route to strengthen other T-cell lineages. γδ T cells share cytotoxic properties with αβ T cells but recognize targets independently of major histocompatibility complex (MHC) and show low alloreactivity, supporting off-the-shelf use in acute myeloid leukemia (AML). Whether such conditioning benefits γδ T cells was unknown. Here, we show that ex vivo venetoclax pretreatment enhances the antileukemic efficacy of therapeutic γδ T cells and chimeric antigen receptor (CAR) γδ T cells. Venetoclax-pretreated γδ T cells displayed increased cytotoxicity and proliferation with reduced exhaustion, yielding superior control of AML blasts and xenografts. These functional gains coincided with elevated mitochondrial content and a fatty acid oxidation metabolic profile. In vivo, venetoclax-pretreated γδ T cells achieved durable disease suppression, and the same conditioning improved CAR γδ T-cell efficacy. Together, these results show that short-term BCL-2 inhibition enhances γδ T-cell cytotoxicity and persistence. Incorporating venetoclax pretreatment into γδ T-cell manufacturing may improve therapeutic efficacy and inform next-generation γδ T-cell therapies for AML.
    Keywords:  Cancer immunotherapy; Hematology; Immunology; Immunotherapy; Leukemias
    DOI:  https://doi.org/10.1172/JCI202932
  28. Br J Haematol. 2026 Jul 23.
    CCAAT/enhancer-binding protein alpha basic leucine zipper in-frame insertion/deletion (CEBPA bZIP-InDel-inf) defines a favourable-prognosis subgroup in CEBPA-mutated acute myeloid leukaemia.
    Yankun Yang, Yuqian Tang, Kun Yang, Ying Zhang, Jirui Tang, Meiting Liang, Yuping Gong.
      This study investigated how cytosine-cytosine-adenine-adenine-thymine (CCAAT)/enhancer-binding protein alpha (CEBPA) mutation sites and types affect the prognosis of acute myeloid leukaemia (AML). It specifically analysed the clinical and genetic features of AML patients harbouring CEBPA basic leucine zipper in-frame insertion/deletion (CEBPA bZIP-InDel-inf) mutations and identified prognostic factors in this subtype. Prognostic factors in CEBPA bZIP-InDel-inf subgroup were examined in depth. Overall survival (OS) and relapse-free survival (RFS) censoring models were built, informative censoring was adjusted using inverse probability of censoring weighting, and stabilized weights were applied in weighted Cox regression analyses. Risk scores for OS and RFS were then developed from multivariable results. Ninety-three patients with CEBPA mutation, 56 had CEBPA bZIP-InDel-inf. Compared with CEBPA bZIP-InDel-inf, CEBPA non-InDel had a worse prognosis. Within the bZIP region, bZIP-InDel-inf also showed better outcomes than other mutation types, especially in double-mutated cases. In weighted multivariate analysis, higher white blood cell count, blast cell count and M4/M5 phenotype independently predicted worse OS, while higher variant allele frequency (VAF), colony stimulating factor 3 receptor (CSF3R) mutation and lower haemoglobin predicted worse RFS. These variables enabled clear OS and RFS risk stratification. CEBPA bZIP-InDel-inf is a favourable CEBPA-mutated AML subtype. Further research is needed to elucidate the role of bZIP-domain-mutated proteins.
    Keywords:  CEBPA mutation; acute myeloid leukaemia; prognosis
    DOI:  https://doi.org/10.1111/bjh.70705
  29. Leukemia. 2026 Jul 23.
    Cumulative disruption of regulatory genes precedes whole-chromosome gains in acute myeloid leukemia.
    Mingxuan Liang, Yan Pan, Nicole Y L Saw, Xiutao Lu, Alexandre Mondaini, Sze P Tsui, Nelson K L Ng, Suet Y Leung, Michael Huen, Anskar Y H Leung, Asif Javed.
      
    DOI:  https://doi.org/10.1038/s41375-026-03069-z
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