bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–12–07
47 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. The promise of menin inhibitors: from approval to triplet regimens.
  2. Impact of donor selection in adverse-risk AML undergoing hematopoietic cell transplantation: A study from the EBMT Acute Leukemia Working Party.
  3. Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure.
  4. Human TET2-mutant clonal hematopoiesis expansion is driven by distinct inflammatory signaling responses in stem cells versus myeloid progeny.
  5. Posttransplant cyclophosphamide versus antithymocyte globulin in patients with cardiovascular comorbidity undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukaemia in first complete remission from unrelated donors: a retrospective matched-pair analysis from the ALWP of the EBMT.
  6. Parallel Evolution of Leukemic Clones in Myeloproliferative Neoplasms.
  7. Clinical outcomes and safety in patients with lower-risk myelodysplastic syndromes treated with imetelstat: Substudy of the phase 3 IMerge trial.
  8. DDX41-mutant myeloid neoplasms defy current prognostic schemes and require a dedicated risk scoring system: a multicenter, retrospective study.
  9. Investigation and management of thrombocytosis without JAK2, CALR or MPL mutations: A British Society for Haematology Guideline.
  10. Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.
  11. Utility of Peripheral Blood Testing for Detection and Surveillance of Clonal Hematopoiesis in Predisposed Individuals (CH-IPI).
  12. Vulnerability of SRSF2 mutated chronic myelomonocytic leukemia to perturbation of cGAS-STING pathway.
  13. Targeted triplet therapies incorporating FLT3 or IDH inhibitors: ready for prime time?
  14. Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
  15. DDX6 undergoes phase separation to modulate metabolic plasticity and chemoresistance.
  16. THRAP3 promotes ferroptosis resistance in acute myelocytic leukemia through SLU7-mediated alternative splicing of GIT2.
  17. Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis.
  18. Frequency and impact of somatic co-occurring mutations on post-transplant outcomes in acute myeloid leukemia: a multicenter registry analysis on behalf of the EBMT ALWP.
  19. Triplet regimens for all: genomically agnostic approaches to improve on HMA + VEN in AML?
  20. Loss of endothelial miR-126 drives age-related decline in hematopoiesis.
  21. Venetoclax/FluBu2 RIC transplant followed by all-oral venetoclax/decitabine maintenance for poor risk MDS/AML.
  22. Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia.
  23. Real-world analysis of CPX-351 in AML-MR: A multicentre study from the MARROW consortium.
  24. Real-world experience with CPX-351 for secondary acute myeloid leukaemia: Comparison with FLAG-IDA in a propensity score matching analysis.
  25. American Society of Hematology 2025 guidelines for treating newly diagnosed acute myeloid leukemia in older adults.
  26. Pig and human adult hematopoietic stem and progenitor cells are overall transcriptionally similar.
  27. Impact of graft-versus-host disease prophylaxis strategies on GvHD-free/relapse-free survival in young adults undergoing unrelated donor allogeneic haematopoietic cell transplantation: A propensity score-matched analysis.
  28. Decoding the molecular drivers of TP53-mutant acute myeloid leukaemia: Clinical implications and prognostic insights.
  29. Studying clonal heterogeneity of acute myeloid leukemia under nutrient and chemotherapy stress.
  30. Updates in low/intermediate-risk MDS.
  31. Demystifying the diagnosis and management of ICUS, CHIP, and CCUS.
  32. The global epidemiology of acute myeloid leukaemia.
  33. Prognostic factors in chronic myeloid leukemia: at diagnosis and for treatment-free remission.
  34. Differences in prognostic value of FLT3 and NPM1 mutations in older and younger patient populations with acute myeloid leukemia.
  35. Engraftment of gene-edited hematopoietic stem cells after antibody-drug conjugate conditioning in nonhuman primates.
  36. Myelofibrosis-associated extramedullary hematopoiesis: Insights into hepatic, pulmonary, and thrombotic complications.
  37. How I Treat Advanced Phases of CML.
  38. Model-based antithymocyte globulin dosing in ex vivo CD34+ selected allogeneic haematopoietic cell transplantation: a single-centre, single-arm, phase 2 study.
  39. Post-HCT maintenance therapy for AML: who, when, why, how long?
  40. Management of iron overload in adult myelodysplastic syndrome.
  41. Impact of fitness categorization according to SIE/SIES/GITMO criteria in therapy-related and AML-MRC receiving CPX-351.
  42. JAK2 wild-type erythrocytosis: concept, differential diagnosis, diagnostic steps, and treatment approaches.
  43. Germline Heterozygous SH2B3 p.Glu78Lys Variant: A Three-Patient Case Series with Myeloproliferative Neoplasms (MPNs).
  44. New age GVHD prophylaxis regimens: what works for what donor and why.
  45. ERK-mTOR crosstalk suppresses Autophagy and upregulates proteasomal degradation pathway to confer Chronic Myeloid Leukemia cells resistant to Imatinib.
  46. Using genomics to refine pediatric AML risk stratification.
  47. Sustained HIV-1 remission after heterozygous CCR5Δ32 stem cell transplantation.
  1. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 599-606
    The promise of menin inhibitors: from approval to triplet regimens.
    Rahul K Thakur, Eunice S Wang.
      Pharmacologic targeting of the menin-KMT2A protein-protein interaction has emerged as a therapeutic breakthrough for acute leukemias harboring KMT2A rearrangements or NPM1 mutations. The first-in-class menin inhibitor (revumenib) achieved accelerated regulatory approval in November 2024 for monotherapy of relapsed/refractory KMT2A rearranged leukemia. Next-generation agents (ziftomenib, bleximenib, enzomenib, BMF-219) have displayed similar composite complete remission rates (20-35%) and overall response rates (45-65%) in heavily pretreated KMT2Ar and NPM1m acute myeloid leukemia (AML) with measurable residual disease (MRD) negativity and prolonged overall survival (5-7 months). While all menin inhibitors result in on-target blast differentiation with clinical sequelae ("differentiation syndrome") in 10% to 20% of patients, not all menin inhibitors are the same, with differing safety, toxicity (heartrate corrected QT interval (QTc) prolongation, cytopenias), and pharmacokinetic profiles. Acquired mutations in the menin gene described in 39% of post-revumenib relapses have not been identified following other inhibitors (ziftomenib, bleximenib), prompting new questions about resistance mechanisms. These promising results swiftly led to the launch of multiple trials of menin inhibitors combined with intensive (cytarabine and anthracycline) and nonintensive (venetoclax and hypomethylating) chemotherapy backbones. To date, these triplets have yielded high response rates (ie, ≥80% in de novo, 50-70% in relapsed) with most patients achieving MRD negativity and prolonged one-year survival. Ongoing/pending phase 3 trials will clarify whether menin blockade should be incorporated into frontline and maintenance regimens for all patients with KMT2A rearranged or NPM1 mutant disease. In the current era, menin inhibition remains a key pillar of the success of precision medicine for AML therapy.
    DOI:  https://doi.org/10.1182/hematology.2025000755
  2. Bone Marrow Transplant. 2025 Nov 29.
    Impact of donor selection in adverse-risk AML undergoing hematopoietic cell transplantation: A study from the EBMT Acute Leukemia Working Party.
    Marta Villalba, Allain-Thibeault Ferhat, Tobias Gedde-Dahl, Gerard Socie, Anne Huynh, Igor Wolfgang Blau, Ibrahim Yakoub-Agha, Didier Blaise, Matthias Eder, Edouard Forcade, Renato Fanin, Jakob Passweg, Charles Crawley, Matthias Stelljes, Friedrich Stölzel, Nicolaus Kroeger, Henrik Sengeloev, Patrice Ceballos, Helene Labussiere-Wallet, Xavier Poiré, Jordi Esteve, Bipin Savani, Arnon Nagler, Simona Piemontese, Jaime Sanz, Mohamad Mohty, Fabio Ciceri.
      We evaluated the influence of donor type in 3006 adults with adverse-risk cytogenetic acute myeloid leukemia (AML) in first complete remission undergoing allogeneic hematopoietic cell transplantation (HCT). Donor types included matched sibling (MSD), matched unrelated (MUD), mismatched unrelated (MMUD), and haploidentical donors. At 2 years, leukemia-free survival, overall survival (OS), and graft-versus-host disease (GVHD)-free/relapse-free survival were 47%, 55%, and 36%. Compared with MSD, OS was inferior with MUD (HR 1.36; 95% CI, 1.1-1.67), MMUD (HR 1.4; 95% CI, 1.07-1.83), and haploidentical grafts (HR 1.33; 95% CI, 1.02-1.73). Haploidentical was associated with lower relapse risk (HR 0.72; 95% CI, 0.53-0.97), but higher non-relapse mortality (NRM) (HR 3.85; 95% CI, 2.44-6.08). All alternative donors showed higher rates of grade II-IV acute GVHD. In 702 patients receiving post-transplant cyclophosphamide (PTCy), survival differences attenuated. However, haploidentical and MMUD showed higher risk of grade III-IV acute GVHD (HR 2.61; 95% CI, 1.04-6.54 and HR 3.74; 95% CI, 1.14-12.24), and haploidentical had increased NRM (HR 3.22; 95% CI, 1.23-8.44), without significant relapse. Findings support safety of alternative donors and reinforce MSD as preferred choice in adverse-risk AML. PTCy mitigates but does not eliminate the risk of donor mismatch.
    DOI:  https://doi.org/10.1038/s41409-025-02751-7
  3. Blood Adv. 2025 Dec 06. pii: bloodadvances.2025018178. [Epub ahead of print]
    Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure.
    Kuo-Kai Chin, Brian J Ball, Yasmin Abaza, Jessica K Altman, Rahul K Thakur, Moiez Ali, Andriy Derkach, Mark B Geyer, Aaron D Goldberg, Tamanna Haque, Meghan C Thompson, Jae H Park, Martin S Tallman, Sheng F Cai, Eunice S Wang, Ibrahim Aldoss, Eytan M Stein.
      Menin inhibitors (MENINi) show promise for relapsed or refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangements (KMT2Ar) and NPM1 mutations (NPM1c). Outcomes after MENINi failure are poorly understood. To characterize the mutational landscape and subsequent outcomes, we conducted a multicenter retrospective study of adults from 4 U.S. centers with R/R AML after MENINi failure (relapse after response or primary refractory). The 84 patients (63% KMT2Ar, n=53; 23% NPM1c, n=19) who received MENINi were heavily pre-treated: 86% (n=72) had prior intensive chemotherapy (IC), 77% venetoclax (VEN, n=67), and 38% (n=32) allogeneic stem cell transplantation. After MENINi failure, 40% of patients (n=34) received supportive care. Of the 60% (n=50) that were treated, common regimens were hypomethylating agent (HMA)/VEN (26%, n=13), clinical trial (26%, n=13), and gilteritinib-based therapy (18%, n=9). The CR/CRi rate for non-trial therapies was 19% (n=7); ORR was 32% (n=12). All CR/CRi occurred with HMA/VEN (n=2, 15%), IC+VEN (n=4, 67%), or MENINi switching (bleximenib to revumenib, n=1, 50%). No FLT3-mutant patients responded to gilteritinib (0/6 gilteritinib-naïve). Median overall survival (mOS) from start of next therapy was 4.4 months; patients who achieved CR/CRi had mOS of 15.4 vs 3.4 months for non-responders (p=0.048). Outcomes after MENINi failure are poor, but responses occur with VEN-based regimens or MENINi switching. FLT3-ITD, WT1, and MEN1 mutations are associated with resistance.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018178
  4. Blood Cancer Discov. 2025 Dec 03.
    Human TET2-mutant clonal hematopoiesis expansion is driven by distinct inflammatory signaling responses in stem cells versus myeloid progeny.
    Hector Huerga Encabo, Giuseppe D'Agostino, Katherine Sturgess, Alice E Lord, Eric D Jong, Alessandra Ferrelli, Aneesh Sharma, Syed A Mian, Khadidja Habel, Miriam Llorian-Sopena, Amirtha Priya Ramesh, Fatihah Mohamad Nor, Helene Foissner, Manuel Garcia-Albornoz, Lynette Graver, Despoina Papazoglou, Steven Ngo, Fernando Anjos-Afonso, Linda Ariza-McNaughton, Gabriella Ficz, Dominique Bonnet.
      Clonal hematopoiesis (CH) increases with age and is associated with severe outcome in the course of infections or tumor development. Understanding the environmental conditions that favor mutant clones and the CH-immune system response to such environments is key to designing therapeutic strategies to stall the expansion of mutant clones and the development of CH-associated pathologies. Using human cells, we unravel a cell-specific and opposite impact of TET2 mutations on hematopoietic stem and progenitor cells (HSPC) compared to their myeloid progeny. Multi-omic analyses reveal that TET2-mutant HSPCs exhibit intrinsic epigenetic silencing of AP-1 transcription factors and a blunted transcriptional adaptation to systemic inflammation. Conversely, monocyte-macrophage trajectory derived from TET2Mut HSCs contributes to exacerbated inflammation. Together, these findings reconcile how TET2-mutant CH can simultaneously promote increased stemness within the HSPC compartment and heightened inflammation through its myeloid progeny, providing mechanistic insight into how TET2-CH expands under inflammatory stress.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0070
  5. Bone Marrow Transplant. 2025 Dec 03.
    Posttransplant cyclophosphamide versus antithymocyte globulin in patients with cardiovascular comorbidity undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukaemia in first complete remission from unrelated donors: a retrospective matched-pair analysis from the ALWP of the EBMT.
    Jan Vydra, Allain-Thibeault Ferhat, Nicolaus Kröger, Tobias Gedde-Dahl, Matthias Eder, Thomas Schroeder, Urpu Salmenniemi, Régis Peffault de Latour, Jakob Passweg, Ibrahim Yakoub-Agha, Alessandro Rambaldi, Robert Zeiser, Matthias Stelljes, Kristina Carlson, Cristina Castilla-Llorente, Alexandros Spyridonidis, Bipin Savani, Fabio Ciceri, Mohamad Mohty.
      We retrospectively analyzed data from the EBMT registry on patients with pretransplant comorbidities associated with cardiovascular risk. Patients who underwent first allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission between 2010 and 2022 from unrelated donors using post-transplant cyclophosphamide (ptCy) or anti-thymocyte globulin (ATG)-based graft-versus-host disease prophylaxis with a history of cardiac disease, arrhythmia, diabetes, obesity or cerebrovascular disease according to the HCT-specific comorbidity index were included. We performed a matched-pair analysis using a propensity score. After matching, 432 patients were included: 313 in the ATG group and 119 in the ptCy group. At 2 years, overall survival was 67.5% (95% CI 61-73.2) and 68.6% (95% CI 56.7-77.8); leukemia-free survival was 60.4% (95% CI 53.8-66.4) and 62.6% (95% CI 50.4-72.6); relapse incidence was 22.1% (95% CI 17-27.7) and 23.2% (95% CI 14.3-33.4); non-relapse mortality was 17.5% (95% CI 13.1-22.4) and 14.1% (95% CI 7.5-22.8), respectively. In conclusion, our study suggests that the use of ptCY for GVHD prophylaxis in patients with preexisting comorbidities associated with cardiovascular risk yields long-term outcomes comparable to those observed with ATG-based approaches.
    DOI:  https://doi.org/10.1038/s41409-025-02766-0
  6. Res Sq. 2025 Nov 17. pii: rs.3.rs-8097141. [Epub ahead of print]
    Parallel Evolution of Leukemic Clones in Myeloproliferative Neoplasms.
    Grant Challen, Tyler Parsons, Aishwarya Krishnan, Infencia Xavier Raj, Andrew Young, David O'Leary, Jason Arand, Maggie Allen, Stephen Oh.
      Myeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional cooperating mutations, the absence of the JAK2V617F variant in some cases of sAML derived from JAK2V617F-mutant MPN suggests alternative mechanisms of transformation. Utilizing patient samples and in vivo modeling, we establish that leukemia-initiating clones driven by TET2 mutations can emerge independently of JAK2-mutant cells and undergo positive selection in the pro-inflammatory MPN environment, leading to parallel disease evolution. Convergent profiling of mouse and human models identified IL-12 and TNFα as candidates providing extrinsic selective pressures and genetic and pharmacological inhibition of these cytokines mitigated the competitive advantage of TET2-mutant cells in an MPN background. These findings unveil therapeutic strategies to potentially prevent leukemic evolution in MPN patients by inhibiting specific cytokine signaling. Our data establish a new paradigm for clonal evolution of blood neoplasms by showing that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones independent of the primary disease.
    DOI:  https://doi.org/10.21203/rs.3.rs-8097141/v1
  7. Br J Haematol. 2025 Nov 30.
    Clinical outcomes and safety in patients with lower-risk myelodysplastic syndromes treated with imetelstat: Substudy of the phase 3 IMerge trial.
    Rami S Komrokji, Valeria Santini, Uwe Platzbecker, Koen Van Eygen, María Díez-Campelo, Raquel de Paz, Guillermo Sanz Santillana, Sylvain Thépot, Maciej Kaźmierczak, Esther Natalie Oliva, Mikkael A Sekeres, Pierre Fenaux, Yazan F Madanat, Michael R Savona, Jennifer Riggs, Sheetal Shah, Ashley L Lennox, Qi Xia, Libo Sun, Tymara Berry, Amer M Zeidan.
      
    Keywords:  QTc; anaemia; clinical trial; efficacy; imetelstat; myelodysplastic syndromes; safety; transfusions
    DOI:  https://doi.org/10.1111/bjh.70266
  8. Leukemia. 2025 Dec 03.
    DDX41-mutant myeloid neoplasms defy current prognostic schemes and require a dedicated risk scoring system: a multicenter, retrospective study.
    Carmelo Gurnari, Hideki Makishima, Arda Durmaz, Enrico Attardi, Ryunosuke Saiki, Alex Bataller, Guilherme Sapinho, Lukasz Gondek, Yasuhito Nannya, Steve Best, Pramila Krishnamurthy, Kar Lok Kong, Yoshiko Atsuta, Senji Kasahara, Kazuma Ohyashiki, Yasushi Miyazaki, Nobuhiro Kanemura, Nobuhiro Hiramoto, Francesco Versino, Maria Julia Montoro, Sara Torres-Esquius, Andres Jerez Cayuela, Miguel López-Esteban, Carolina Martínez-Laperche, Hussein Awada, Valeria Visconte, Courtney D DiNardo, Maria Teresa Voso, Amy E DeZern, Guillermo Garcia-Manero, Austin G Kulasekararaj, Jaroslaw P Maciejewski, Seishi Ogawa.
      DDX41-mutant myeloid neoplasia (MN) is characterized by unique clinical-molecular characteristics and prognosis. However, it is poorly understood how DDX41 mutational constellations drive MN outcomes. We leveraged collaborative resources to test the new 2022 MN diagnostic and prognostic schemes and account for the diverse mutational configurations of DDX41-mutant MN. Diagnostic re-classification from 2016 to 2022 schemes showed an overall shift of 14.9% and 29.7% for DDX41-mutant MDS and AML, respectively. Current prognostic systems (IPSS-R/M and ELN 2017/22) showed poor applicability to DDX41-mutant MN when compared to wild-type counterparts. Dissecting all possible DDX41 configurations, we assigned the greatest prognostic impact to R525H somatic and germline truncating hits. The former impacted most survival outcomes, while the latter were enriched in AML, independently predicting leukemic evolution. Such features had synergistic effects, albeit with different treatment interactions, and were included in DDX41-specific multivariable outcome models, which alleviated the shortcomings of the current prognostic MN algorithms. We here show that current prognostic tools are not able to adequately assess leukemic evolution and survival outcomes in DDX41-mutant MN. Additional risk factors inherent to this MN subentity hold a prognostic significance beyond the consideration of traditional disease-specific variables, substantiating the need for a dedicated risk scoring system.
    DOI:  https://doi.org/10.1038/s41375-025-02814-0
  9. Br J Haematol. 2025 Dec 04.
    Investigation and management of thrombocytosis without JAK2, CALR or MPL mutations: A British Society for Haematology Guideline.
    BSH Committee
      
    Keywords:  diagnosis; myeloproliferative; platelets; thrombocytosis; triple negative
    DOI:  https://doi.org/10.1111/bjh.70260
  10. bioRxiv. 2025 Nov 24. pii: 2025.11.21.689510. [Epub ahead of print]
    Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.
    Aditi Chatterjee, Moaath K Mustafa Ali, Christopher M Bailey, Yuchen Liu, Donald Small, Catherine C Smith, Elie Traer, Yin Wang, Giovannino Silvestri, Maria R Baer.
      FLT3 inhibitor efficacy in AML with FLT3-ITD is short-lived, frequently due to new mutations, most commonly in NRAS . Sphingosine kinase 1 (SPHK1), which phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), is upregulated and localized to the plasma membrane in RAS -mutated cells. We studied S1P and FLT3 co-targeting to overcome FLT3 inhibitor resistance in NRAS -mutated FLT3-ITD AML cells. NRAS -mutated FLT3-ITD AML cell lines and patient blasts were treated with FLT3 inhibitors and/or S1P receptor (S1PR) modulators. FLT3 inhibitor sensitivity was assessed by immunoblotting, cytotoxicity and apoptosis assays. Co-treatment was also assessed in vivo in an orthotopic mouse model. Downstream RAS and SPHK1 effectors were measured by immunoblotting and qRT-PCR. The S1PR modulators fingolimod (FTY720) and mocravimod (KRP-203) resensitized FLT3-ITD-expressing MOLM-14 and MV4-11 human AML cells with G12D, G12S, Q61K or Q61H, but not G12C, and patient blasts with G13D or G13V NRAS mutations to FLT3 inhibitors. Moreover, FTY720 co-treatment resensitized G12D NRAS -mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS -mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy of these combinations.
    DOI:  https://doi.org/10.1101/2025.11.21.689510
  11. Blood. 2025 Nov 10. pii: blood.2024028042. [Epub ahead of print]
    Utility of Peripheral Blood Testing for Detection and Surveillance of Clonal Hematopoiesis in Predisposed Individuals (CH-IPI).
    Enrico Attardi, Nathan Gray, Sara Lewis, Michelle Eubanks Boals, Passant Shaker, Lili Kotmayer, Sushree S Sahoo, Peng Li, Erica F Andersen, Jian Zhao, Lucilla Pizzo, Joseph H Oved, Rohith Jesudas, Ulrike M Reiss, Richa Sharma, Georgios E Christakopoulos, Senthil Velan Bhoopalan, Clifford M Takemoto, Alyssa L Kennedy, Maria Teresa Voso, Guolian Kang, Marcin W Wlodarski.
      We evaluated 108 pediatric patients with bone marrow failure and leukemia predisposition for presence of clonal hematopoiesis in peripheral blood (PB) and bone marrow (BM). We found robust PB-BM concordance for mutations but decreased sensitivity in PB for chromosomal abnormalities.
    DOI:  https://doi.org/10.1182/blood.2024028042
  12. Blood Adv. 2025 Dec 04. pii: bloodadvances.2025017005. [Epub ahead of print]
    Vulnerability of SRSF2 mutated chronic myelomonocytic leukemia to perturbation of cGAS-STING pathway.
    Yanan Chen, Koon Chuen Chan, Chun Fung Sin, Lichuan Zheng, Dandan Wang, Lingge Tu, Fangfang He, Wan Hei Jeffrey Hui, Hoi Ki Leung, Leslie Kar Fai Chan, Sze Pui Tsui, Hoi-Yi Chan, Alvin Chun Hang Ma, Anskar Yh Leung, Xuan Sun.
      Chronic myelomonocytic leukemia (CMML) is characterised by monocytosis in blood and bone marrow and natural progression to acute myeloid leukemia (AML) in up to 30% of patients. The mutation landscape of CMML has been reported, and animal models that recapitulate its clinicopathologic features and progression are needed. We report a CMML zebrafish model based on transgenic SRSF2P95H expression that closely resembled the human disease. Hematological assessment of the transgenic animals showed myelodysplasia, monocytosis, and leukemia transformation. Transcriptomic analysis confirmed global splicing alterations and identified inflammatory phenotypes associated with activation of the cGAS-STING pathway. DNA damage, R-loop and dsDNA accumulation were evident. Inhibition of R-loop formation or cGAS-STING axis significantly reduced gene expression associated with inflammation and immune activation and mitigated the leukemia phenotype. The inflammatory effects and their response to treatment were recapitulated in human hematopoietic stem and progenitor cells (HSPC). Collectively, our findings showed a pathogenetic link between SRSF2P95H and cGAS-STING activation in CMML and its vulnerability to therapeutic intervention.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017005
  13. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 592-598
    Targeted triplet therapies incorporating FLT3 or IDH inhibitors: ready for prime time?
    Himachandana Atluri, Yasmin Abaza, Jessica K Altman.
      Combination therapies in acute myeloid leukemia (AML) are an area of current investigation due to the potential of overcoming resistance by targeting multiple pathways simultaneously. Triplet therapies combining hypomethylating agents, venetoclax, and targeted inhibitors are emerging as a promising therapy for older patients with AML unfit for intensive chemotherapy. These regimens have predominantly been studied in FLT3- and IDH1/2-mutated AML with attainment of high rates of measurable residual disease-negative composite remissions. Notably, patients with FLT3-internal tandem duplication and IDH1-mutated AML appear to garner a significant benefit from combination treatment due to poor duration of response to hypomethylating agents/venetoclax alone. While effective, the need to remain on indefinite therapy for individuals who are not stem cell transplant candidates and dose optimization/de-escalation strategies remain critical concerns. Herein, we aim to review the current treatment landscape of newly diagnosed and relapsed/refractory FLT3- and IDH1/2-mutated AML and the role of triplet regimens in these molecular subgroups.
    DOI:  https://doi.org/10.1182/hematology.2025000754
  14. Nat Metab. 2025 Dec 05.
    Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
    Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, J Darren Stuart, Paul A Grimsrud, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.
      Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene-gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.
    DOI:  https://doi.org/10.1038/s42255-025-01410-x
  15. Nat Commun. 2025 Dec 02.
    DDX6 undergoes phase separation to modulate metabolic plasticity and chemoresistance.
    Hongjie Bi, Wei Li, Lili Ren, Honghai Zhang, Lei Dong, Anthony Chan, Xueer Wang, Lu Yang, Xiaoxu Zhang, Meilin Xue, Hanjun Qin, Xiwei Wu, Johanna Ten Hoeve-Scott, Bin Zhang, Ling Li, Mark Wunderlich, James C Mulloy, Steven T Rosen, Jianjun Chen, Xiaobo Li, Chun-Wei Chen, Rui Su.
      Stress granules (SGs) and processing bodies (PBs), assembled via liquid-liquid phase separation (LLPS), are critical for spatial regulation of gene expression in the cytoplasm. However, their roles in tumorigenesis remain poorly understood. Here, we show DEAD-box helicase 6 (DDX6) as the most promising vulnerability in acute myeloid leukemia (AML) through in vitro and in vivo CRISPR screenings using a specialized library targeting RNA-binding proteins enriched in SGs and PBs. Knockout (KO) of DDX6 significantly delays leukemogenesis with minimal impact on normal hematopoiesis. Importantly, the functions of DDX6 in AML depend largely on its ability to trigger LLPS and PB assembly. Mechanistically, PBs serve as "reservoirs" for the mRNAs interacting directly with DDX6 and having low GC content. DDX6 KO leads to rapid PB dissolution and release of PB-enriched mRNAs, such as BCAT1, into the cytosol, where these transcripts undergo degradation. By reducing BCAT1 levels, DDX6 KO reprograms amino acid metabolism and sensitizes AML cells to cytarabine chemotherapy.
    DOI:  https://doi.org/10.1038/s41467-025-66966-4
  16. Nat Commun. 2025 Dec 01.
    THRAP3 promotes ferroptosis resistance in acute myelocytic leukemia through SLU7-mediated alternative splicing of GIT2.
    Dan Wang, Zhixiang Wu, Siyang Liu, Jing He, Haixia Zhang, Pan Chen, Minghua Yang.
      Induction of ferroptosis is a potential strategy to eliminate chemotherapy-resistant acute myeloid leukemia (AML) cells. Here, we investigate the role and mechanism of thyroid hormone receptor-associated protein 3 (THRAP3) in ferroptosis of AML cells. We show that high expression of THRAP3 is correlated with a poor prognosis in AML patients. THRAP3 knockdown suppresses AML cell proliferation, and delays orthotopic and subcutaneous tumor growth in male mice; however, THRAP3 overexpression exerts the opposite roles. THRAP3 overexpression promotes resistance of AML cells to RSL3/erastin-induced ferroptosis via inhibiting iron accumulation and promoting GSH synthesis. Mechanistically, THRAP3 recruits SLU7 homolog, splicing factor (SLU7) to facilitate GIT ArfGAP 2 (GIT2) Exon14 skipping. Inhibition of GIT2 Exon14 skipping reverses THRAP3-induced ferroptosis resistance in vitro and in vivo. Altogether, THRAP3 contributes to ferroptosis resistance of AML cells via interaction with SLU7 to trigger GIT2 Exon14 skipping, which suggests THRAP3 to be a therapeutic target for AML.
    DOI:  https://doi.org/10.1038/s41467-025-66931-1
  17. Sci Adv. 2025 Dec 05. 11(49): eaea7451
    Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis.
    Longfei Gao, Desmond Dickson, Huijuan Feng, Chaolin Zhang, Lei Ding.
      Self-renewing hematopoietic stem cells (HSCs) generate all blood cells and give rise to long-term reconstitution of the hematopoietic system after transplantation, but the molecular mechanisms that specifically regulate HSCs remain poorly defined. Here, we found that HSCs displayed a distinct messenger RNA alternative splicing pattern and preferentially expressed Rbfox2, an alternative splicing regulator, compared with multipotent progenitors (MPPs). Deletion of Rbfox2 from the hematopoietic compartment specifically depleted HSCs, but not progenitors in the adult bone marrow. Rbfox1 did not function redundantly with Rbfox2 in HSCs. Mechanistically, Rbfox2 loss led to proteostasis stress, including increased protein synthesis rate and accumulated misfolded/unfolded protein contents, in HSCs, but not in progenitors. Small molecules that restore proteostasis rescued HSC defects in Rbfox2-deficient mice. Our work thus reveals that HSCs, but not progenitors, selectively rely on Rbfox2 for their self-renewal and maintenance.
    DOI:  https://doi.org/10.1126/sciadv.aea7451
  18. Bone Marrow Transplant. 2025 Dec 05.
    Frequency and impact of somatic co-occurring mutations on post-transplant outcomes in acute myeloid leukemia: a multicenter registry analysis on behalf of the EBMT ALWP.
    Ali Bazarbachi, Jacques-Emmanuel Galimard, Iman Abou Dalle, Myriam Labopin, Jaime Sanz, He Huang, Jiri Mayer, Carlos Solano, Bruno Lioure, Laimonas Griskevicius, Johan Maertens, Maija Itälä-Remes, Ain Kaare, Maria-Pilar Gallego-Hernanz, Gesine Bug, Josep-Maria Ribera, Alain Gadisseur, Christoph Schmid, Mi Kwon, Xavier Poiré, Paola Coccia, Manuel Jurado Chacón, Frédéric Baron, Charles Craddock, Eolia Brissot, Arnon Nagler, Fabio Ciceri, Mohamad Mohty.
      Acute myeloid leukemia (AML) includes genetically defined subsets. In allogeneic hematopoietic cell transplantation (allo-HCT), the frequency and prognosis of gene-gene interactions may differ from those of patients treated with chemotherapy alone. In this study, adult patients (N = 952) with AML allografted between 2015 and 2023, with available next generation sequencing (NGS) at diagnosis were included. Most frequent mutations were DNMT3A (24%), FLT3-ITD (21%), NPM1 (21%), RUNX1 (16%), NRAS (16%), TET2 (14%), and IDH2 (12%). Multiple correspondence analysis identified distinct groups of co-occurring mutations. Outcome analysis was performed on 646 AML patients allografted in first complete remission (CR1). Six non-overlapping groups were constructed: 1) TP53 mutation (N = 47); 2) NPM1 mutation (N = 129); 3) FLT3-ITD and/or DNMT3A mutation (N = 128); 4) SRSF2 and/or ASXL1 and/or RUNX1 mutation (SAR group) (N = 132); 5) IDH1 and/or IDH2 and/or TET2 mutation (N = 43); and 6) all ten genes unmutated (N = 167). In multivariable analysis, TP53 mutation, adverse karyotype, and age negatively affected leukemia-free survival (LFS) and overall survival (OS). OS was additionally negatively affected when the ten genes were unmutated. Notably, outcomes were excellent for SAR mutations (2-year LFS 76%, OS 84%), indicating allo-HCT in CR1 can overcome their adverse risk at diagnosis.
    DOI:  https://doi.org/10.1038/s41409-025-02770-4
  19. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 607-613
    Triplet regimens for all: genomically agnostic approaches to improve on HMA + VEN in AML?
    William Nicol, Andrew H Wei.
      Combined hypomethylating agent (HMA) plus venetoclax (Ven) therapy enables most older patients with acute myeloid leukemia (AML) to achieve clinical remission. Key objectives are now aimed at developing new triplet combinations to circumvent mechanisms of resistance and extend remission longevity and, by extension, survival. Genomically agnostic approaches combine hypomethylating agents and venetoclax (HMA-Ven) with novel agents directed at oncogenic pathways critical for leukemic cell survival, proliferation, metabolism, or differentiation. Challenges faced in the development of new HMA-Ven triplets include competition from targeted inhibitors, biological heterogeneity of AML, potential for additive toxicity, reduced efficacy from modifications to the HMA-Ven backbone, and the higher bar for success in older AML beyond the current standard of care.
    DOI:  https://doi.org/10.1182/hematology.2025000756
  20. Haematologica. 2025 Dec 04.
    Loss of endothelial miR-126 drives age-related decline in hematopoiesis.
    Dandan Zhao, Le Xuan Truong Nguyen, Xubo Gong, Fang Chen, Xiaoli Zhao, Min-Hsuan Chen, Guido Marcucci, Bin Zhang.
      Aging profoundly alters the bone marrow (BM) microenvironment and impairs hematopoietic stem cell (HSC) function. Here, we identify decrease of miR-126 derived from arteriolar endothelial cells (ECs) as a key mechanism of impaired HSC self-renewal capacity during aging. In young BM, arteriolar ECs express high levels of miR-126, which is transferred to HSCs and supports these cells' homeostasis and functional integrity. Using young and aged wild-type, endothelial-specific miR-126 knockout (EC-miR-126 KO), EC-Spred1 knockout (a functional model of EC-miR-126 upregulation), and EC/Sca-1 dual fluorescent reporter mice, we show that age-related increase in inflammatory cytokines (such as TNFα) reduces EC miR-126 expression and in turn drives loss of miR-126high CD31+Sca-1high EC-lined arterioles in the aging BM niche. Loss of arterioles in turn decreases the EC miR-126 supply to HSCs, leading to expansion of HSCs with limited self-renewal capacity. Remarkably, administration of a synthetic miR-126 mimic oligonucleotide restores EC-HSC communication and rescues aging-related HSC dysfunction. Our findings uncover a novel, non-cell-autonomous mechanism of HSC aging and highlight EC-derived miR-126 as a promising therapeutic target to rejuvenate hematopoiesis.
    DOI:  https://doi.org/10.3324/haematol.2025.288736
  21. Blood Adv. 2025 Dec 05. pii: bloodadvances.2025018631. [Epub ahead of print]
    Venetoclax/FluBu2 RIC transplant followed by all-oral venetoclax/decitabine maintenance for poor risk MDS/AML.
    Jacqueline S Garcia, Haesook T Kim, H Moses Murdock, Anna Bosch-Vilaseca, Kevin M Panaro, Felicia Lim, Jade Fiorilla, Elise Auriemma, Jennifer Brock, Mahasweta Gooptu, Vincent T Ho, Corey S Cutler, Roman M Shapiro, Amar H Kelkar, Gregory A Abel, Daniel J DeAngelo, Richard M Stone, Denbaa Bat-Erdene, Jeremy Adam Ryan, Geoffrey Fell, Anthony Letai, Jerome Ritz, R Coleman Lindsley, Joseph H Antin, Robert J Soiffer.
      To improve the tolerability of post-transplant maintenance and outcomes despite poor risk disease genetics, we conducted a phase 1 study of venetoclax/FluBu2 RIC transplantation with tacrolimus/methotrexate GVHD prophylaxis followed by all-oral venetoclax/decitabine-cedazuridine (ven/dec-c) maintenance in poor-risk MDS/AML patients (N=30). 58% had prior venetoclax exposure and 63% were TP53-mutated; 15/19 had TP53 multi-hit state. At a median of +55 days, pre-emptive maintenance therapy with venetoclax (400 mg on days 1-14) and dec-c (decitabine 35 mg/cedazuridine 100 mg on days 1,3,5 or 1,2,3) was initiated for eight 42-day cycles in 26/30 (87%) patients (remaining 3 relapsed early, 1 withdrew). On maintenance, grade 3-4 neutropenia (96%) occurred though infections were rare (N=2). No DLTs occurred. 6-month acute GVHD grade II-IV rate was 13%. 1-year moderate/severe chronic GVHD rate was 31%. At a median follow up of 25.1-months (range,15-33), median OS and PFS were not reached. On maintenance, 2-year OS was 77% (95%CI,55-89), PFS 62% (95%CI,38-79), NRM 0%, and cumulative incidence of relapse 38% (95%CI,18-59). Exploratory studies identified 96% had pre-transplant NGS-MRD+, favorable survival in those with non-TP53 MRD+, and delayed conversion on maintenance in 11/18 (61%) in those with TP53 MRD+. PROs assessed in first 6-months of maintenance were stable except for emotional function, which improved (P=0.008). Trial is registered at clinicaltrials.gov/NCT03613532.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018631
  22. Blood Cancer Discov. 2025 Dec 05.
    Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia.
    Mark Hartmann, Maximilian Schönung, Jovana Rajak, Valentin Maurer, Ling Hai, Katharina Bauer, Mariam Hakobyan, Sina Stäble, Jens Langstein, Laura Jardine, Roland Roelz, Sheila Bohler, Eleonora Khabirova, Abdul-Habib Maag, Dominik Vonficht, Dirk Lebrecht, Kathrin M Bernt, Kai Tan, Changya Chen, Fatemeh Alikarami, Julia Meyer, Jun Wang, Tobias Boch, Viktoria Flore, Pavlo Lutsik, Michael D Milsom, Simon Raffel, Christian Buske, Simon Haas, Muzlifah Haniffa, Jan-Philipp Mallm, Sam Behjati, Marc-Jan Bonder, Stefan Frohling, Elliot Stieglitz, Charlotte M Niemeyer, Joschka Hey, Christian Flotho, Christoph Plass, Miriam Erlacher, Matthias Schlesner, Daniel B Lipka.
      Persistent fetal gene expression in childhood neoplasms is usually explained by a maturation block originating in the prenatal phase. In contrast, reactivation of fetal genes in adult malignancies is considered a consequence of oncofetal reprogramming (OFR) and is associated with aggressive disease. By reconstructing epigenetic ontogeny in juvenile myelomonocytic leukemia (JMML), we identified a postnatal maturation state of JMML stem cells with high transcriptional plasticity indicative of OFR in high-risk disease. Similarly, post-natal activation of oncogenic signaling by inducible Ptpn11E76K mutation in mice, triggered molecular plasticity and reactivation of fetal gene expression. Integrative multi-omics analysis revealed aberrant CD52 expression as a feature of high-risk JMML stem cells. Anti-CD52 treatment depleted JMML stem cells and blocked disease propagation in xenograft models. Our results challenge the prevailing maturation-block model of pediatric leukemogenesis and establish RAS-associated stem-cell plasticity as a determinant of OFR and potential therapeutic vulnerabilities in high-risk JMML.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0246
  23. Br J Haematol. 2025 Dec 03.
    Real-world analysis of CPX-351 in AML-MR: A multicentre study from the MARROW consortium.
    Daniel T Peters, Deedra Nicolet, Yazan F Madanat, Jesus Gonzalez-Lugo, Alex Ambinder, Onyee Chan, Charles E Foucar, Kieran D Sahasrabudhe, Justice Ameyi, Krzysztof Mrózek, Tara Lin, Najla Al-Ali, Jeffery Lancet, Bianca Barredo, Lauren G Banaszak, Michael J Hochman, Brittany K Ragon, Christine M McMahon, Tamanna Haque, Alice S Mims, Ann-Kathrin Eisfeld, Joshua F Zeidner.
      CPX-351 is a standard front-line induction regimen for newly diagnosed acute myeloid leukaemia (AML) with myelodysplasia-related changes (AML-MRC). The 2022 International Consensus Classification (ICC) and World Health Organization (WHO) classifications redefine AML with myelodysplasia-related (AML-MR) to include myelodysplasia-related mutations as well as cytogenetic abnormalities. Clinical outcomes of patients treated with CPX-351 within these refined AML-MR classifications remain unclear. We conducted a retrospective, multicentre study of 235 adults with newly diagnosed AML-MR treated with CPX-351 across seven US academic centres. Patients were stratified by age (younger: <60 vs. older: ≥60 years) and AML-MR subgroup: cytogenetics (AML-MRc), molecular (AML-MRm) and antecedent haematological disorder (AML-AHD). Outcomes included complete remission (CR) and CR with incomplete recovery (CR/CRi), rates of allogeneic haematopoietic stem cell transplant (alloHSCT) and overall survival (OS). The overall CR/CRi rate of CPX-351 was 52%, with no difference by age. AML-MRm had the highest CR/CRi rate (57%). Among CR/CRi responders, 55% underwent alloHSCT (<60 years: 53% vs. ≥60 years: 57%). Median OS was 13.8 months with no significant difference by age. Younger AML-MRm patients had longer median OS compared with older AML-MRm patients (38.0 vs. 19.5 months; p = 0.05). Favourable outcomes in AML-MRm, particularly in younger patients, support molecular classification in guiding therapy and selectively extending CPX-351 use beyond older adults.
    Keywords:  AML‐MR; CPX‐351; secondary‐type mutations
    DOI:  https://doi.org/10.1111/bjh.70274
  24. Br J Haematol. 2025 Dec 04.
    Real-world experience with CPX-351 for secondary acute myeloid leukaemia: Comparison with FLAG-IDA in a propensity score matching analysis.
    Maria Agustina Perusini, Ana Flavia Patiño, Claire Andrews, Sarit E Assouline, Joseph M Brandwein, Signy Chow, Gizelle Popradi, David Sanford, Lynn Savoie, Lalit Saini, Bambace Nadia, Dina Khalaf, Andre C Schuh, Karen Yee, Vikas Gupta, Dawn Maze, Steven M Chan, Aaron D Schimmer, Waleed Sabry, Hassan Sibai.
      
    Keywords:  CPX‐351; Secondary Acute Myeloid Leukemia (sAML); intensive chemotherapy; real world evidence
    DOI:  https://doi.org/10.1111/bjh.70275
  25. Blood Adv. 2025 Nov 25. pii: bloodadvances.2025017934. [Epub ahead of print]
    American Society of Hematology 2025 guidelines for treating newly diagnosed acute myeloid leukemia in older adults.
    Mikkael A Sekeres, Ryan J Mattison, Andrew S Artz, Maria R Baer, Chong Chyn Chua, Roberta Demichelis-Gomez, Pamela C Egan, Luke Fletcher, Charles E Foucar, Jacqueline S Garcia, Linda Gilberto, Andrés Gómez-De León, Jeffrey E Lancet, Kah Poh Loh, Luca Malcovati, Bernard Lawrence Marini, Uwe Platzbecker, Mohamed L Sorror, Sara Tinsley-Vance, John Treitz, Maria Jose Oliveros, Sara Ibrahim, Yetiani Roldan, Gordon H Guyatt, Romina Brignardello-Petersen.
      Older adults with acute myeloid leukemia (AML) represent a cancer population in whom disease-based risk factors, comorbidities, patient goals, and treatment risks and benefits influence treatment recommendations. These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians and other health professionals in their decisions about management of AML in older adults. ASH formed a multidisciplinary guideline panel, including patient representatives, that minimized bias from conflicts of interest. Clarity Research Group at McMaster University supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including Evidence-to-Decision frameworks, to assess evidence and make recommendations. The panel agreed on 9 critical clinical recommendations for managing AML in older adults, mirroring real-time practitioner-patient conversations: the decision to pursue antileukemic treatment vs. best supportive management; traditional induction and post-remission therapy vs. hypomethylating agent or low-dose cytarabine, or combinations with venetoclax; the role and duration of post-remission therapy; combinations with venetoclax vs. monotherapy; the use of targeted therapy, including IDH and FLT3 inhibitors, in appropriate patients; the role of hematopoietic stem cell transplantation in non-favorable prognosis AML; and the role of transfusion support for patients no longer receiving antileukemic therapy. Key recommendations of these guidelines include treatment over best supportive care; venetoclax-based regimens over monotherapies; and incorporation of FLT3 inhibitors into traditional induction and post-remission therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017934
  26. Exp Hematol. 2025 Dec 01. pii: S0301-472X(25)00623-X. [Epub ahead of print] 105334
    Pig and human adult hematopoietic stem and progenitor cells are overall transcriptionally similar.
    Emma Bailey, Foteini Kalampalika, Raúl Sánchez-Lanzas, Justin Barclay, Amanda Jiménez-Pompa, Jun Wang, Miguel Ganuza.
      Over the recent years, pigs have re-emerged as an alternative source of organs for xenotransplantation into humans with the promise to overcome a worldwide shortage of human donors. Xenotransplantation still faces critical issues with immune rejection that could be potentially solved by the generation of lymphohematopoietic chimeras. Moreover, pig hematopoietic stem and progenitor cells (HSPCs) can constitute themselves an unlimited source of HSPCs for lifesaving HSPC transplantation in bone marrow failure and post-chemotherapy, among other cell therapies. The generation of these hematopoietic chimeras requires a profound study of pig hematopoiesis including pig hematopoietic stem and progenitor cells (HSPCs). Importantly, via single cell RNA sequencing of pig bone marrow cells we identified pig HSPC populations transcriptionally similar to those in humans and many common transcriptional regulators of hematopoiesis evolutionarily preserved in erythromyeloid and lymphoid differentiation. This supports that hematopoiesis in pigs is hierarchically organized and regulated in a very similar fashion as in humans. We also provided a sorting strategy for the identification and isolation of several putative pig HSPC populations which should open a new means to functionally study pig hematopoiesis.
    DOI:  https://doi.org/10.1016/j.exphem.2025.105334
  27. Br J Haematol. 2025 Dec 05.
    Impact of graft-versus-host disease prophylaxis strategies on GvHD-free/relapse-free survival in young adults undergoing unrelated donor allogeneic haematopoietic cell transplantation: A propensity score-matched analysis.
    Nihar Desai, Sergio Rodriguez Rodriguez, Eshrak Al-Shaibani, Tommy Alfaro Moya, Igor Novitzky-Basso, Arjun Datt Law.
      Young adults (YAs) undergoing allogeneic haematopoietic stem cell transplantation (HSCT) represent a unique population with distinct medical and psychosocial needs. Optimizing graft-versus-host disease (GvHD) prophylaxis in this population remains critical to improving outcomes. We performed a retrospective analysis of YAs undergoing unrelated donor HSCT using a contemporary Center for International Blood and Marrow Transplant Research (CIBMTR) dataset. GvHD-free, relapse-free survival (GRFS) at 24 months was evaluated across three GvHD prophylaxis strategies: Group A (post-transplant cyclophosphamide [PTCy] + calcineurin inhibitor [CNI] + mycophenolate mofetil [MMF]), Group B (CNI + methotrexate [MTX]/MMF), and Group C (CNI + MTX/MMF + anti-thymocyte globulin [ATG]). A propensity score-matched (PSM) analysis was conducted to adjust for baseline differences. A total of 1387 YA patients were included. In the total cohort, 24-month GRFS was 58.9% (confidence intervals [95% CI], 53-64) in Group A, 32.2% (95% CI, 29-36) in Group B and 44.2% (95% CI, 39-49) in Group C (p < 0.001). On multivariable analysis (MVA), both Group A (hazard ratio [HR] = 0.44; 95% CI, 0.35-0.54) and Group C (HR = 0.79; 95% CI, 0.70-0.90) showed improved GRFS compared to Group B. In the propensity score-matched cohort, GRFS at 24 months remained higher in the PTCy group (58.2%, 95% CI, 52-64) versus the CNI-MTX/MMF ± ATG group (32.9%, 95% CI, 27-39; p < 0.001), with PTCy independently associated with improved GRFS (HR = 0.48; 95% CI, 0.40-0.60; p < 0.001). PTCy-based prophylaxis also reduced non-relapse mortality (NRM), with no significant differences in relapse or overall survival (OS) between groups. In this large, retrospective analysis, PTCy was associated with significantly improved GRFS and reduced NRM in YAs undergoing unrelated donor HSCT. These findings support the use of PTCy-based regimens in this population and warrant prospective evaluation.
    Keywords:  GvHD prophylaxis; PTCy; allogeneic transplant; young adults
    DOI:  https://doi.org/10.1111/bjh.70269
  28. Br J Haematol. 2025 Nov 30.
    Decoding the molecular drivers of TP53-mutant acute myeloid leukaemia: Clinical implications and prognostic insights.
    Lin-Ya Wang, Hai-Tao Gao, Qiang Fu, Qian Jiang, Hao Jiang, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Xiao-Jun Huang, Fei-Fei Tang.
      This study aimed to investigate the distinct clinical characteristics and molecular features of TP53-mutant acute myeloid leukaemia (AML) patients. We retrospectively analysed 193 TP53-mutant AML patients. Better responses were observed in patients treated with the venetoclax in combination with hypomethylating agent (VEN + HMA) regimen compared to those receiving the '3 + 7' regimens (composite complete remission [CRc], 53.8% vs. 30.2%; p = 0.018). TP53 V272 mutation was associated with a lower relapse rate (0% vs. 35.2%; p = 0.041). The single hit group exhibited superior OS compared to the multi-hit group (the median overall survival [OS]: 14.3 months vs. 10.8 months; p = 0.029). TP53-mutant AML patients with CEBPA bZIP in-frame mutations showed prolonged OS (the median OS: 25.2 months vs. 13.8 months; p = 0.036). Better prognoses were also shown in patients with RUNX1-RUNX1T1 fusion gene (the median OS: 31.1 months vs. 13.7 months; p = 0.002). Multivariate analysis identified three significant prognostic factors for OS: RUNX1-RUNX1T1 fusion gene (hazard ratio [HR] = 0.23, 95% confidence interval [CI], 0.08-0.63; p = 0.005), RUNX1 mutation (HR = 1.84; 95% CI, 1.14-2.96; p = 0.012) and FLT3-ITD mutation (HR = 3.14; 95% CI, 1.80-5.47; p = 0.001). In conclusion, molecular factors matter in influencing the prognosis of TP53-mutant AML patients. Among them, TP53 mutation sites merit particular attention.
    Keywords:  TP53 mutation; acute myeloid leukaemia; genetic characteristics
    DOI:  https://doi.org/10.1111/bjh.70271
  29. Blood Adv. 2025 Dec 06. pii: bloodadvances.2025016618. [Epub ahead of print]
    Studying clonal heterogeneity of acute myeloid leukemia under nutrient and chemotherapy stress.
    Christina Mayerhofer, Eve Crompton, Ernst Mayerhofer, Trine A Kristiansen, Tsuyoshi Fukushima, Samuel Keyes, Azeem Sharda, Dan Li, Carmen Da Silva, Deumaya Shrestha, Anna Kiem, Tobias Feuchtinger, David T Scadden, Peter Grant Miller.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025016618
  30. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 699-708
    Updates in low/intermediate-risk MDS.
    Hetty E Carraway.
      Low- and intermediate-risk myelodysplastic syndromes (LR-MDS and Int-MDS, respectively) are characterized by ineffective hematopoiesis, along with the presence of at least 10% dysplasia in one cell line, accompanied by a low number and depth of peripheral blood cytopenias, a low bone marrow blast percentage, and a score of ≤0 on the Molecular International Prognostic Scoring System (IPSS-M). The information gleaned from mutational profiles at the time of myelodysplastic syndrome (MDS) diagnosis and over subsequent time points help with classification and prognosis, guiding therapeutic decisions. In LR-MDS, these decisions are initially focused on improving symptom control and optimizing hematologic parameters. New therapeutic options to reduce the red blood cell (RBC) transfusion burden have emerged since 2020 and include luspatercept and imetelstat. Erythropoiesis-stimulating agents and lenalidomide also address anemia and are generally recommended to start at the time of transfusion dependency, although emerging data suggest that an earlier start of these interventions might offer clinical benefits. Patients can derive years of benefit from these approaches in LR-MDS, but despite these therapies, ultimately MDS will evolve into higher-risk MDS (HR-MDS)/acute myeloid leukemia. Even though most LR-MDS patients present with anemia, patients can have isolated thrombocytopenia for which thrombopoietin receptor analogues can be used if blasts are low. Immunosuppressive therapy such as antithymocyte globulin is favored in the hypocellular MDS setting. Dose-modified hypomethylating agent use can be considered for LR-MDS, although neither overall survival (OS) nor progression-free survival (PFS) has been shown to improve with this approach. Targeted therapy directed to the presence of an IDH1 mutation is U.S. Food and Drug Administration (FDA) approved for the rare IDH1 mutated MDS (<10% of the time) and consideration to use an IDH2 inhibitor for IDH2 mutated MDS (<5% of the time) is reasonable. Interestingly, IDH mutations seem to appear with increased frequency in older patients and in patients with underlying autoimmune/rheumatological disorders.1.
    DOI:  https://doi.org/10.1182/hematology.2025000768
  31. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 682-690
    Demystifying the diagnosis and management of ICUS, CHIP, and CCUS.
    Zhuoer Xie, Dae Hyun Lee, Doris K Hansen, Sanam Loghavi.
      Precursor states such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance, carry distinct risks for progression to myeloid neoplasms and age-related comorbidities. While biologically distinct, idiopathic cytopenia of undetermined significance is also a differential diagnostic consideration for these precursor lesions. Through 3 illustrative cases, we highlight the diagnostic complexity and clinical relevance of these entities, emphasizing the need for integrated clinical, morphologic, and molecular assessment to guide individualized patient care. Emerging evidence suggests that CHIP contributes not only to hematopoietic stem cell aberrations and potential myeloid neoplasia but also to cardiovascular disease and solid-tumor outcomes, reinforcing its significance as a systemic biomarker. We summarize the current risk stratification tools and ongoing clinical trials aimed at modulating inflammation and clonal dynamics in CH-associated conditions. We also outline our approach from our Clonal Hematopoiesis Clinic, which incorporates surveillance, preventive care, and clinical trial enrollment. Establishing standardized diagnostic criteria, harmonizing trial frameworks, and formally incorporating CHIP into hematology, oncology, cardiology, and survivorship paradigms will be essential to reducing long-term morbidity and improving patient outcomes.
    DOI:  https://doi.org/10.1182/hematology.2025000766
  32. Nat Rev Clin Oncol. 2025 Dec 05.
    The global epidemiology of acute myeloid leukaemia.
    Firas El Chaer, Jan P Bewersdorf, Maximilian Stahl, Amer M Zeidan.
      Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with an incidence that increases with age and varies widely across regions owing to differences in risk factors, diagnostic capabilities, recording in cancer registries and access to health care. Despite improved outcomes over the past decade owing to the approvals of various novel therapies as well as improvements in supportive care and better access to, and safety of, allogeneic haematopoietic stem cell transplantation, progress has largely been confined to high-income countries. Patients in low-income or middle-income countries often remain reliant on older cytotoxic regimens, when available. The incidence of AML in high-income countries has increased over the past decades owing to population ageing in many of these countries as well as improved access to diagnostics. By contrast, AML has a lower incidence but is associated with higher mortality and morbidity in most low-income or middle-income countries. Multiple risk factors predispose individuals to AML, including germline variants, environmental and lifestyle factors, prior exposure to chemotherapy and radiation, and certain medical conditions and comorbidities. In this Review, we highlight global trends in the incidence, risk factors, demographic disparities and treatment-related outcomes of patients with AML across diverse geographical regions. We also outline the urgent need to improve the cancer registry infrastructure, expand global surveillance, leverage artificial intelligence for data analysis and promote equitable access to clinical trials.
    DOI:  https://doi.org/10.1038/s41571-025-01099-7
  33. Haematologica. 2025 Dec 04.
    Prognostic factors in chronic myeloid leukemia: at diagnosis and for treatment-free remission.
    Delphine Rea.
      Although chronic myeloid leukemia (CML) is defined by the sole presence of the BCR::ABL1 fusion gene-the genetic event underlying the genesis of the disease-the diversity of clinical outcomes, even in the tyrosine kinase inhibitors (TKI) era, reveals that its apparent biological homogeneity is, in fact, misleading, both between and within individuals. Increasing knowledge of biological diversity through advances in cellular analytical tools and expansion of the TKI arsenal to address this heterogeneity are key factors in the path to a better disease control and ultimately cure. In this review, we focus on well-established and novel modifiable and non-modifiable prognostic factors of CML at diagnosis and for treatment-free remission, with particular emphasis on those that are easy to use in clinical practice. We will discuss how these factors may help shape therapeutic choices. Finally, we will highlight innovative research avenues aiming at improving prognostication of CML.
    DOI:  https://doi.org/10.3324/haematol.2025.287756
  34. medRxiv. 2025 Nov 17. pii: 2025.11.16.25340236. [Epub ahead of print]
    Differences in prognostic value of FLT3 and NPM1 mutations in older and younger patient populations with acute myeloid leukemia.
    Claudio A Mosse, Michele LeNoue-Newton, Julie A Lynch, Amy M Perkins, Fern Fitzhenry, Kathryn M Pridgen, Freneka Minter, Mia Levy, Michael E Matheny.
      The prognostic value of nucleophosmin-1 ( NPM1 ) and fms-like tyrosine kinase 3 ( FLT3 ) mutations has been well-established in adult patients but is less clear in geriatric patients. This retrospective cohort study assessed adult patients with acute myeloid leukemia (AML) who received FLT3 and/or NPM1 testing treated at any Veterans Health Administration (VHA) facility or at Vanderbilt University Medical Center (VUMC) between January 2006 and December 2016. The primary analysis compared time to all-cause death among patients with AML based on FLT3 and NPM1 mutation status, age (<65 years, ≥65 years), and cytogenetic risk group (unfavorable, intermediate/normal, favorable). The study population (n=766) (mean age 59.71 ± 16.6 years, 45.96% ≥65 years) had a mutation rate of 19.8% for FLT3 and 22.1% for NPM1 . Age was a significant factor in overall survival (median OS: 24.28 vs. 8.18 months, p<0.001), as was cytogenetic risk status (median OS: favorable group not reached, intermediate/normal 17.61m vs. unfavorable 6.77m, p<0.001). The most favorable prognostic group ( FLT3 -/ NPM1 +) among older patients showed worse OS (15.21 months) than did the poor prognostic group ( NPM1 -/ FLT3 -) among younger patients (18.43 months). Among the older cohort, FLT3 and NPM1 mutation status, favorable karyotype, and CCI were not identified as prognostic factors. In the full cohort, using Cox proportional hazard regression and LASSO analyses for age, FLT3 and NPM1 mutation status, cytogenetic risk group, treatment site, race, primary payor, and Charleston Comorbidity Index (CCI), age (HR 65y vs 35y/=2.44, 95% CI 1.61-3.68, p<0.001) was the strongest risk factor in AML.
    DOI:  https://doi.org/10.1101/2025.11.16.25340236
  35. Blood Adv. 2025 Dec 01. pii: bloodadvances.2025017838. [Epub ahead of print]
    Engraftment of gene-edited hematopoietic stem cells after antibody-drug conjugate conditioning in nonhuman primates.
    Jason David Murray, Teresa K Einhaus, Stefan Radtke, Katharine J Bar, Christopher William Peterson, Hans-Peter Kiem.
      Hematopoietic stem cell (HSC) gene therapies provide lifelong benefit in numerous hematological diseases and disorders, but safety and toxicity remain a critical barrier for routine application. In the setting of immunodeficiency syndromes and infectious diseases such as human immunodeficiency virus (HIV) infection, conditioning regimens may exacerbate immune dysfunction, blunting or impairing overall efficacy. Here, we conduct a head-to-head comparison of two novel antibody drug conjugates (ADC) with a pyrrolobenzodiazepine (PDB) payload for autologous transplantation in rhesus macaques: ADCs targeting either CD117 or CD45 and benchmarked against the clinical standard busulfan. We quantified extent of myeloablation and immunosuppression, time to hematopoietic recovery, long-term engraftment of CCR5 CRISPR-edited autologous HSC, and resistance to infection when challenged with increasing concentrations of an HIV-like virus. Both ADCs enabled engraftment of CRISPR-edited HSCs, although with lower levels of long-term editing compared to busulfan. We observed myeloablation with similar times to hematopoietic recovery and preserved lymphocyte counts with all three conditioning regimens, but neither ADC conditioning nor busulfan enabled sufficient CCR5 editing for viral immunity. While these results only apply to the specific ADC conditioning protocols tested here, they are a step towards developing targeted strategies to engraft cells with therapeutic edits and highlight the need for further refinement of antibody-based selection.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017838
  36. Blood Rev. 2025 Nov 28. pii: S0268-960X(25)00100-6. [Epub ahead of print] 101355
    Myelofibrosis-associated extramedullary hematopoiesis: Insights into hepatic, pulmonary, and thrombotic complications.
    Idoroenyi Amanam, Salman Otoukesh, Vinod Pullarkat, Stephen Forman, Guido Marcucci, Monzr Al Malki, Haris Ali.
       BACKGROUND: Primary myelofibrosis (PMF), the most aggressive of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is characterized by progressive marrow fibrosis, ineffective hematopoiesis, and a pro-inflammatory milieu. These pathobiologic features drive extramedullary hematopoiesis (EMH) and confer heightened risks for hepatic, pulmonary, and thrombotic complications, particularly in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT).
    OBJECTIVE: Drawing on our institutional transplant experience in PMF, we review the pathophysiology, clinical manifestations, and management of EMH-related complications to optimize outcomes in this complex patient population.
    METHODS: We synthesized current literature on EMH in MPNs and integrated contemporary data on hepatic portal hypertension, pulmonary hypertension, splanchnic vein thrombosis, and transplant-related complications. Key insights from recent European Society for Blood and Marrow Transplantation (EBMT) registry data are highlighted.
    RESULTS: Portal hypertension affects 3-18 % of patients with myeloproliferative neoplasms (MPNs), driven by intrahepatic sinusoidal infiltration, splenic hyperdynamic circulation, and splanchnic thrombosis. Splanchnic vein thrombosis often precedes overt MPN diagnosis, with JAK2V617F detected in a substantial proportion of affected patients. Pulmonary complications-including extramedullary hematopoiesis (EMH), pulmonary hypertension, and peri-engraftment respiratory failure-contribute meaningfully to non-relapse mortality in the transplant setting. Ruxolitinib, reduced-intensity conditioning, and spleen-directed strategies have improved engraftment kinetics and mitigated graft-related complications in myelofibrosis patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). Institutional observations are incorporated throughout to contextualize hepatic, pulmonary, and vascular manifestations of EMH in contemporary practice.
    CONCLUSION: These institutional observations complement published data and emphasize that EMH-related hepatic, pulmonary, and vascular complications are biologically active yet potentially reversible when clonal disease control is achieved. EMH-associated complications in PMF require a multidisciplinary management approach tailored to disease biology and transplant considerations. Advances in cytokine modulation, conditioning strategies, and emerging antifibrotic agents hold promise for improving patient outcomes.
    Keywords:  Allogeneic transplantation; Extramedullary hematopoiesis; Myelofibrosis; Portal hypertension; Pulmonary hypertension; Splanchnic thrombosis
    DOI:  https://doi.org/10.1016/j.blre.2025.101355
  37. Blood. 2025 Dec 02. pii: blood.2024026510. [Epub ahead of print]
    How I Treat Advanced Phases of CML.
    Michael J Mauro.
      Advanced phases of Philadelphia chromosome positive (Ph+) chronic myeloid leukemia, classically encompassing de novo presentation of accelerated phase disease and blast phase disease (myeloid and lymphoid 'blast crisis') as well as progression to these from antecedent chronic phase disease, have diminished in incidence but remain a challenge. Despite continued development of additional and novel kinase inhibitors of BCR::ABL1, global limitations on access to diagnostics and therapy persist and account for continued incidence of advanced disease at initial presentation as well as progressive disease. Evolution in defining risk through clinical and molecular characterization should increase ability to identify emerging advanced disease, minimize progression and improve treatment of resistant chronic phase and blast phase disease. While BCR::ABL1 tyrosine kinase inhibition remains central in advanced disease, combination therapy with conventional and novel chemotherapy, immunotherapy, and allogeneic stem cell transplantation provide best long-term outcomes.
    DOI:  https://doi.org/10.1182/blood.2024026510
  38. Lancet Haematol. 2025 Dec;pii: S2352-3026(25)00293-5. [Epub ahead of print]12(12): e956-e965
    Model-based antithymocyte globulin dosing in ex vivo CD34+ selected allogeneic haematopoietic cell transplantation: a single-centre, single-arm, phase 2 study.
    Michael Scordo, Miguel-Angel Perales, Audrey Mauguen, Andrew Lin, Binni Kunvarjee, Maria Paes Pena, Devin Mcavoy, Linh Khanh Nguyen, Molly Hogan, Nancy Chapman, Jennifer Bieler, Christina Cho, Boglarka Gyurkocza, Andrew C Harris, Barbara Spitzer, Richard J O'Reilly, Ann A Jakubowski, Richard J Lin, Esperanza B Papadopoulos, Ioannis Politikos, Doris M Ponce, Brian C Shaffer, Gunjan L Shah, Roni Tamari, Sergio A Giralt, Jaap-Jan Boelens, Kevin J Curran.
       BACKGROUND: Ex-vivo CD34+ selected allogeneic haematopoietic cell transplantation (HCT) provides favourable chronic graft-versus-host disease (GVHD)-free relapse-free survival but is limited by delayed immune reconstitution and early non-relapse mortality. High anti-thymocyte globulin (ATG) exposure after HCT has been associated with delayed CD4+ T-cell immune reconstitution, increased non-relapse mortality, and poor overall survival.
    METHODS: We report the final analysis of a single-centre, phase 2 trial investigating pharmacokinetic model-based ATG (targeting <20 AU × d/mL post-HCT exposure) in participants of any age undergoing ex vivo CD34+ selected allogeneic HCT after myeloablative conditioning for haematological malignancies. Two myeloablative conditioning regimens were used at the discretion of the treating physician: the chemotherapy-based regimen (target cumulative exposure of 65 mg × h/L busulfan, 140 mg/m2 melphalan, and 150 mg/m2 fludarabine) and a high-dose total-body irradiation-based regimen (included total-body irradiation [1375 cGy], thiotepa [10 mg/kg], and cyclophosphamide [100 mg/kg]). The primary objective was an improvement in CD4+ immune reconstitution (>50 cells per μL at two consecutive timepoints by day +100) in at least 32% of the per protocol population. This study was registered with ClinicalTrials.gov (NCT04872595) and is completed.
    FINDINGS: Between June 14, 2021, and Nov 28, 2023, we enrolled 59 participants with haematological malignancies. Among evaluable participants (n=56), the median age was 55 years (IQR 30-63), 34 (61%) were male, 22 (39%) were female, 44 (79%) had myeloid malignancies, and 44 (79%) had received chemotherapy-only myeloablative conditioning. The median estimated ATG exposure after HCT was 10 AU × d/mL (IQR 9-11). CD4+ immune reconstitution was reached in 39 (70%) of 56 participants, meeting the study's primary endpoint. The most common grade 3 or worse adverse events were infections (103 [40%] of 259 events) and oral or gastrointestinal events (44 [17%] of 259 events). Grade 5 adverse events occurred in three participants including secondary graft failure (n=1) and multi-organ failure (n=2), with a total of four treatment-related deaths among participants.
    INTERPRETATION: These results demonstrate that model-based ATG dosing promotes robust CD4+ immune reconstitution after ex vivo CD34+ selected allogeneic HCT, underscoring the potential of pharmacokinetically guided ATG as a strategy to optimise immune recovery in myeloablative, calcineurin inhibitor-free transplantation for haematological malignancies.
    FUNDING: US National Cancer Institute, Memorial Sloan Kettering Cancer Center.
    DOI:  https://doi.org/10.1016/S2352-3026(25)00293-5
  39. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 531-536
    Post-HCT maintenance therapy for AML: who, when, why, how long?
    Mark Levis.
      Patients with acute myeloid leukemia (AML) often undergo allogeneic hematopoietic cell transplantation (HCT) as it represents a highly effective treatment to prevent relapse of their disease. While HCT is an important part of curative therapy for many AML patients, post-HCT relapse still occurs, and so post-HCT maintenance therapy is offered to some patients-often without any reliable evidence supporting its use. More and more molecularly targeted drugs are emerging in the field, and while there is randomized data supporting the use of FLT3 inhibitors in this setting, no other drug class has been convincingly shown to benefit these patients (yet). In acknowledgment of the fact that clinicians will continue to offer post-HCT maintenance in the hope of improving outcomes, this review focuses on the data (or lack thereof) directly supporting this practice, as well as some of the pitfalls that can be encountered with these drugs when used as maintenance.
    DOI:  https://doi.org/10.1182/hematology.2025000746
  40. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 87-95
    Management of iron overload in adult myelodysplastic syndrome.
    Heather A Leitch, Rena Buckstein.
      The clinical benefits of iron overload (IOL) management in hereditary anemias, including organ preservation and dramatically improved overall survival (OS), are widely accepted. Adult myelodysplastic syndrome (MDS) patients are older and may have comorbidities, treatments to extend OS are limited, and the clinical benefits of IOL management have been more challenging to demonstrate due to little prospective data in this population. However, current prognostic systems identify MDS patients with reasonable life expectancy who may benefit from IOL management. Half of MDS patients ultimately become dependent on red blood cell transfusion and develop transfusional IOL. Considerable preclinical and clinical data have accumulated indicating the adverse impact of IOL on multiple cellular and clinical end points and a clinical benefit to IOL management in MDS, which should be considered in some patients. Here we provide an overview of salient data in the usual (nonhematopoietic stem cell transplant) clinical MDS setting, summarize mechanisms of iron toxicity including increased radiologically detectable organ stores and redox-active iron-mediated tissue damage, furnish strategies for the identification of IOL, and suggest a framework for IOL severity and IOL reduction. We review which patients are appropriate for IOL management, recommend an appropriate time to intervene, discuss evidence supporting a clinical benefit to IOL management, and recommend how to off-load iron. We identify data gaps for future study and forecast future tools that may become available to minimize IOL toxicity in MDS.
    DOI:  https://doi.org/10.1182/hematology.2025000691
  41. Blood Adv. 2025 Dec 04. pii: bloodadvances.2025017089. [Epub ahead of print]
    Impact of fitness categorization according to SIE/SIES/GITMO criteria in therapy-related and AML-MRC receiving CPX-351.
    Raffaele Palmieri, Fabio Guolo, Luana Fianchi, Felicetto Ferrara, Paola Minetto, Maria Paola Martelli, Carola Riva, Patrizia Chiusolo, Michela Rondoni, Saveria Capria, Clara Minotti, Federica Pilo, Salvatore Perrone, Andrea Corbingi, Francesco Grimaldi, Giulia De Luca, Carla Fili, Caterina Alati, Francesco Mannelli, Federica Lessi, Francesco Marchesi, Lorenzo Brunetti, Debora Capelli, Anna Lina Piccioni, Calogero Vetro, Fanny Erika Palumbo, Carla Mazzone, Alessandra Sperotto, Giovanni Luzi, Michelina Dargenio, Sabrina Mariani, Marco Cerrano, Antonino Mulè, Ambra Di Veroli, Elisa Meddi, Federico Moretti, Cristina Papayannidis, Alessandro Isidori, Antonella Ferrari, Sara Galimberti, Daniela Cilloni, Massimo Breccia, Francesco Lanza, Michele Gottardi, Roberto Cairoli, Anna Candoni, Livio Pagano, Elisabetta Todisco, Roberto Massimo Lemoli, Adriano Venditti, Francesco Buccisano.
      CPX-351, a novel liposomal formulation of cytarabine and daunorubicine, represents the standard of care in fit patients with myelodysplasia-related changes (AML-MRC) and therapy-related Acute Myeloid Leukemia (tAML). Considering its better safety profile than conventional intensive chemotherapy, we investigated its cost/benefit ratio, in terms of overall survival and of mortality, in a large multicentric series of AML-MRC and tAML receiving CPX-351 outside clinical trials between 2019 and 2022. Patients were classified in fit or unfit to intensive chemotherapy through a comprehensive evaluation of age, comorbidities and performance status by adopting SIE/SIES/GITMO criteria. Disease risk was defined according to the ELN2017 classification. Before treatment start, 328/403 (81.4%) were classified as fit, 75/403 (18.6%) as unfit. Three hundred and ninety-six had a full genetic/cytogenetic profile with 17 (4%) being categorized as favorable risk, 162 (41%) intermediate risk, and 217 (55%) adverse risk according to ELN2017. After induction, 230/403 patients (57.1%) achieved a complete remission, with no differences between fit (57.3%) and unfit (56%). However, the two groups significantly differed in terms of survival (median overall survival of 18 months vs 8 months for fit and unfit patients) and of 28- and 100-day mortality (4.6% vs 10.7% at 28 days and 14.3% vs 32% at 100-days for fit and unfit patients, respectively). In conclusion, the SIE/SIES/GITMO criteria discriminated patient subgroups with different short- and long-term outcomes after treatment with CPX-351. The update or design of dedicated fitness criteria could represent a future and valid strategy to optimize the use of this specific treatment.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017089
  42. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 183-190
    JAK2 wild-type erythrocytosis: concept, differential diagnosis, diagnostic steps, and treatment approaches.
    Natasha Szuber, Ayalew Tefferi, Naseema Gangat.
      JAK2 unmutated/wild-type erythrocytosis is a prevalent condition encompassing a wide spectrum of hereditary and acquired entities. It is conventionally defined by the same hemoglobin/hematocrit thresholds as for polycythemia vera. Incidence has been reported to be between 0.13% and 4.1%. The most clinically relevant step in the workup of erythrocytosis is the exclusion of polycythemia vera through JAK2 mutation screening. Consideration of relative polycythemia, normal outliers, and the influence of erythropoietic drugs and comorbidities is also imperative. Distinguishing long-standing from newly acquired erythrocytosis further streamlines the diagnostic process. Hereditary erythrocytosis (HE) is lifelong and typically associated with a positive family history. Subnormal serum erythropoietin (EPO) suggests an EPO receptor mutation. Otherwise, oxygen tension at 50% hemoglobin saturation (p50) discerns between high oxygen-affinity hemoglobin variants, 3-bisphosphoglycerate deficiency, methemoglobinemia, and PIEZO1 mutations (low p50) and germline oxygen-sensing pathway/other rare mutations (normal p50). Acquired erythrocytosis results from hypoxia-driven factors (eg, cardiopulmonary, altitude, renal artery stenosis) and other mechanisms of EPO overproduction (eg, EPO-secreting tumors) or hypersensitivity, as well as EPO-independent mechanisms. Drugs (eg, sodium glucose co-transporter-2 inhibitors, testosterone) are also common causes. Idiopathic erythrocytosis is a diagnosis of exclusion, increasingly attributed to underlying genetic mutations/polymorphisms. There are currently no evidence-based treatment guidelines. Low-dose aspirin and/or phlebotomy (with frequency determined by symptom relief) might be considered on an individualized basis in the presence of hyperviscosity symptoms, cardiovascular comorbidities, and/or a history of thrombosis. Aggressive control of cardiovascular risk factors is recommended in all. A graphic abstract representation is provided in Figure 1.
    DOI:  https://doi.org/10.1182/hematology.2025000704
  43. Exp Hematol. 2025 Nov 29. pii: S0301-472X(25)00622-8. [Epub ahead of print] 105333
    Germline Heterozygous SH2B3 p.Glu78Lys Variant: A Three-Patient Case Series with Myeloproliferative Neoplasms (MPNs).
    G Iaquinta, A Laganà, A Tamburini, C Tatarelli, P Chiusolo, E Rossi, M Rossi, M Ragazzo, E Savino, M Breccia, P Grammatico.
       BACKGROUND: We investigated the clinical significance of a rare germline SH2B3 variant (c.232G>A; p.Glu78Lys) identified by targeted next-generation sequencing (NGS) in patients with myeloproliferative neoplasms (MPNs).
    METHODS: Among around 330 patients, three heterozygous carriers (≈1.0% prevalence) were identified by NGS and confirmed as germline (buccal swab) by Sanger sequencing (SS).
    RESULTS: Two of the carriers presented with essential thrombocythemia (ET) that progressed to secondary myelofibrosis (SMF) and one presented with primary myelofibrosis (PMF) that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. The p.Glu78Lys substitution localizes in the N-terminal dimerization domain (DD) of SH2B3. This germline variant is rare in population databases (allele frequency ∼1.1-2.2 per 1,000 inhabitants), and is currently classified as a variant of uncertain significance (VUS). In silico predictions were discordant, while structural modelling predicts disruption of critical hydrogen-bonding at the dimer interface, suggesting potential functional impact.
    CONCLUSIONS: Although heterozygosity alone appears insufficient to drive disease, the enrichment of this variant in our MPN cohort and its occurrence in relatively young patients support a possible low-penetrance predisposition role. Functional assays, larger case-control series, and assessment of genetic/epigenetic modifiers are needed to define pathogenicity and clinical utility.
    TEASER ABSTRACT: We report on a rare heterozygous germline SH2B3 (c.232G>A; p.Glu78Lys) in three patients with myeloproliferative neoplasms. Structural modelling suggests a disrupted SH2B3 dimerization for this variant, which may have a potential functional impact. Although heterozygosity alone appears insufficient to drive disease, we suggest that SH2B3 p.Glu78Lys variant may determine a possible low-penetrance predisposition that warrants functional validation and broader screening.
    Keywords:  SH2B adapter protein 3 (SH2B3), lymphocyte adapter protein (LNK), myeloproliferative neoplasms (MPNs), c.232G>A; p.Glu78Lys
    DOI:  https://doi.org/10.1016/j.exphem.2025.105333
  44. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 458-464
    New age GVHD prophylaxis regimens: what works for what donor and why.
    Mahasweta Gooptu, John Koreth.
      Allogeneic hematopoietic stem-cell transplantation is a curative modality for hematologic malignancies, bone marrow failure syndromes, hemoglobinopathies, and other nonmalignant disorders. Graft-versus-host disease (GVHD)-in its acute or chronic form-is an important transplant complication. The effective prevention of GVHD is crucial to the success of allotransplantation. Acute GVHD is mediated by the recognition of recipient antigens by donor T lymphocytes, with the subsequent activation and proliferation of T cells and establishment of an inflammatory cytokine cascade. Chronic GVHD is mediated by T-cell, B-cell, and macrophage activation with eventual inflammation and fibrosis. Standard approaches for GVHD prevention have been calcineurin-inhibitor (CNI) based, while newer approaches have focused on adding in-vivo T-cell modulation to a CNI backbone with antimetabolites such as posttransplant cyclophosphamide (PTCy), checkpoint blocking agents such as abatacept, or mammalian target of rapamycin (mTOR) inhibition with sirolimus. Still other approaches focus on blocking T-cell trafficking to target organs via integrin blockade (vedolizumab), cytokine blockade (JAK inhibitors), and B-cell blockade for chronic GVHD prevention. The use of PTCy and abatacept have improved allotransplantation safety and efficacy with human leukocyte antigen (HLA)-mismatched as well as HLA-matched donors, thus expanding the donor pool greatly for patients of all ancestries, and ushering in a new era in transplantation where donors are available for almost every patient.
    DOI:  https://doi.org/10.1182/hematology.2025000737
  45. Exp Hematol. 2025 Nov 28. pii: S0301-472X(25)00619-8. [Epub ahead of print] 105330
    ERK-mTOR crosstalk suppresses Autophagy and upregulates proteasomal degradation pathway to confer Chronic Myeloid Leukemia cells resistant to Imatinib.
    Rajdeep Roy, Tamalika Paul, Pritam Kumar Das, Samraj Sinha, Siddhartha Sankar Ray, Maitreyee Bhattacharyya, Nabendu Biswas.
      Drug resistance remains a critical barrier in effective cancer therapy. Previously, we demonstrated that expression of anti-apoptotic protein XIAP, contributes to the development of TRAIL resistance in chronic myeloid leukemia (CML) cells. However, upon acquiring drug resistance (K562R and KCL22R), XIAP degradation shifted from the lysosomal to the proteasomal pathway. Consistently, XIAP expression was markedly elevated in tumor samples compared to normal controls and was significantly higher in Imatinib-failure (IMA-FL) patients than in Imatinib-responsive (IMA-RP) counterparts within the patient cohort. Moreover, we have found that proteasomal activity increased in imatinib resistance cells and lysosomal pathway is inhibited. Mechanistically, we found that H₂O₂-induced activation of the ERK-mTOR axis suppressed autophagy in resistant cells, facilitating this shift in degradation pathway. Very interestingly, dual intervention by restoring autophagic flux via mTOR inhibition and inducing XIAP degradation using H2O2 reverted Imatinib resistance in K562R cells. Thus, our findings uncover a novel ERK-mTOR-axis for upregulation of proteasomal degradation of XIAP which could be targeted to overcome Imatinib-resistance by combinatorial inhibition of mTOR and XIAP in CML. This study holds the promise of a new therapeutic strategy for overcoming drug resistance in cancer.
    Keywords:  Cell signaling; Leukemia; Lysosome; Proteasome; ROS
    DOI:  https://doi.org/10.1016/j.exphem.2025.105330
  46. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 270-278
    Using genomics to refine pediatric AML risk stratification.
    Martina Pigazzi, Soheil Meshinchi, Franco Locatelli.
      In the past 20 years, advances in genomic technologies have greatly improved our understanding of pediatric acute myeloid leukemia (AML). Today, cytogenetic tests can detect structural changes in approximately 75% of cases and remain a main tool for assessing risk. Recent technologies, such as next-generation sequencing, are revealing additional structural alterations (cryptic fusions) and mutations that often cooperate to influence disease biology and treatment response. This evolving genetic landscape has identified unique childhood subtypes of AML defined by specific fusions, such as NUP98::NSD1, CBFA2T3::GLIS2, and varied KMT2A rearrangements, which are linked to distinct clinical outcomes. Emerging data also point to the poor prognosis associated with certain subtypes of NPM1, like the NPM1-D isoform. Additionally, mutations in genes like WT1, DNMT3A, and TP53, the latter of which are rare in childhood AML, may influence patients' outcomes, particularly when occurring in combination. Targeted therapies, including FLT3, BCL2, and menin inhibitors, are beginning to reshape treatment, offering more personalized approaches. However, integrating these drugs effectively into the patient's treatment strategy remains challenging due to the genetic complexity and rarity of pediatric AML. Key issues ahead include identifying which genetic features truly affect outcomes, using this information to personalize therapy, predicting who will benefit from targeted drugs, and choosing the best markers to track disease response over time. Looking forward, collaborative efforts are urgently needed to validate pediatric-specific biomarkers, test novel drug combinations, and link genetic data to clinical outcomes to design trials and future treatment strategies.
    DOI:  https://doi.org/10.1182/hematology.2025000714
  47. Nature. 2025 Dec 01.
    Sustained HIV-1 remission after heterozygous CCR5Δ32 stem cell transplantation.
    Christian Gaebler, Samad Kor, Kristina Allers, Michela Perotti, David Mwangi, Karolin Meixenberger, Kirsten Hanke, Timo Trenkner, Tom Kraus, Yequin Sha, Carmen Arentowicz, Stanley Odidika, Nikolai Grahn, Rachel Scheck, Naomi Perkins, Marion Pardons, Vanessa Igbokwe, Victor Corman, Thomas Burmeister, Olga Blau, Gülüstan Sürücü, Axel Pruß, Christian G Schneider, Gerd Klausen, Jürgen Sauter, Florian Klein, Leif E Sander, Jörg Hofmann, Lam Vuong, Lars Bullinger, Livius Penter, Henning Gruell, Daniel B Reeves, Philipp Schommers, Angelique Hoelzemer, Martin Obermeier, Igor W Blau, Thomas Schneider, Olaf Penack.
      HIV cure is exceptionally rare, documented in only six cases among the estimated 88 million individuals who have acquired HIV since the epidemic's onset1-6. Successful cures, including the pioneering Berlin patient, are limited to individuals receiving allogeneic stem cell transplants (allo-SCT) for hematological cancers. HIV resistance from stem cell donors with the rare homozygous CCR5 Δ32 mutation was long considered the main mechanism for HIV remission without antiretroviral therapy (ART), but recent reports highlight CCR5-independent mechanisms as important contributors to HIV cure6-8. Here, we provide new evidence for this conceptual shift, reporting exceptionally long, treatment-free HIV remission following allo-SCT with functionally active CCR5. A heterozygous CCR5 wild-type/Δ32 male living with HIV received allo-SCT from an HLA-matched unrelated heterozygous CCR5 wild-type/Δ32 donor as treatment for acute myeloid leukemia. Three years after allo-SCT, the patient discontinued ART. To date, HIV remission has been sustained for over six years with undetectable plasma HIV RNA. Reservoir analysis revealed intact proviral HIV before transplantation, but no replication-competent virus in blood or intestinal tissues after allo-SCT. Declining or absent HIV-specific antibody and T cell responses support the absence of viral activity. High antibody-dependent cellular cytotoxicity (ADCC) activity at the time of transplantation may have contributed to HIV reservoir clearance. These results demonstrate that CCR5Δ32-mediated HIV resistance is not essential for durable remission, underscoring the importance of effective viral reservoir reductions in HIV cure strategies.
    DOI:  https://doi.org/10.1038/s41586-025-09893-0
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