bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–01–18
25 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. MDS/AML and AML with myelodysplasia-related gene mutations: clinical and molecular similarities.
  2. Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia - a HARMONY study.
  3. Stratifying Survival: The Role of Social Determinants of Health on AML Outcomes by ELN 2022 Criteria.
  4. CHEK2 loss endows chemotherapy resistance to hematopoietic stem cells.
  5. Modulation of the clonal burden in patients with lower-risk myelodysplastic neoplasms treated with imetelstat.
  6. Hypomethylating agents in vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS): A systematic review.
  7. Randomized phase 3 trial of Ropeginterferon alfa-2b versus surveillance after tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia (ENDURE/CML-IX).
  8. Dual FLT3/PIM inhibitor dapolsertib in acute myeloid leukemia: results from the phase 1/2 DIAMOND-01 trial.
  9. Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness.
  10. Compartmentalized inflammatory landscape and macrophage plasticity regulate Tet2+/- mediated clonal hematopoiesis.
  11. Characteristics and prognostic significance of myelodysplasia-related features in VEXAS syndrome.
  12. CSF1R marks a subset of foetal haematopoietic multipotent progenitor cells with acute myeloid leukaemia propagation properties.
  13. First-line tagraxofusp leads to durable responses and prolonged survival in adults with blastic plasmacytoid dendritic cell neoplasm regardless of fitness level.
  14. Drivers of clinical resistance to venetoclax and hypomethylating agents in acute myeloid leukemia and strategies for improving efficacy.
  15. Integrative spatial multi-omics reveal niche-specific inflammatory signaling and differentiation hierarchies in AML.
  16. A Murine Bispecific Antibody Efficiently Redirects T Cells Against Calr Mutated Stem Cells In Vivo.
  17. MYST acetyltransferases are a targetable therapeutic vulnerability in SETBP1-mutant leukemia.
  18. FBXO11 suppression rewires an NPM1-centered interactome influencing the progression of myelodysplastic syndrome.
  19. Antileukemic therapies for older adults with AML ineligible for conventional therapy: systematic review & meta-analysis.
  20. An inflammatory and quiescent HSC subpopulation expands with age in humans.
  21. Evaluation of dual BCL-2/BCL-XL inhibition in AML preclinical models with and without prior venetoclax therapy.
  22. Modeling donor age and type trade-offs for personalized selection in allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide prophylaxis.
  23. VEXAS syndrome: a comprehensive review of pathogenesis, clinical spectrum, and therapeutic strategies.
  24. PU.1-Activated Genomic Regions Define Low-risk MDS Subsets Characterized by Immune Dysregulation and Disease Progression.
  25. Re-Evaluating Donor Selection Priorities for Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide.
  1. Blood Adv. 2026 Jan 13. pii: bloodadvances.2025018408. [Epub ahead of print]
    MDS/AML and AML with myelodysplasia-related gene mutations: clinical and molecular similarities.
    Emma L Boertjes, Tim Grob, Adil Salim Abdullah Al Hinai, Berna H Beverloo, Jurjen Versluis, François G Kavelaars, Melissa Rijken, K G Compagne, Claudia A J Erpelinck-Verschueren, Mathijs Arnoud Sanders, Elodie C G Stoetman, D Hanekamp, Patrycja Gradowska, Gert J Ossenkoppele, Bart J Biemond, Markus G Manz, Thomas Pabst, Mojca Jongen-Lavrencic, Bob Löwenberg, Peter J M Valk.
      Acute myeloid leukemia (AML) is driven by diverse genetic abnormalities. We investigated clinical and molecular differences between clinically-defined secondary AML following antecedent MDS (sAML), molecularly-defined secondary type AML (st-AML), molecularly-defined MDS/AML (st-MDS/AML;10-19% blasts) and other newly diagnosed AML (de novo AML). We also examined the prognostic value of molecular measurable residual disease (MRD) detection in st-AML. This retrospective cohort study included 2,684 intensively treated AML patients. Bone marrow and peripheral blood samples collected at diagnosis (n=2,684) and complete remission (CR) (n=436) were sequenced using a 54-gene panel targeting the most frequently mutated genes in AML. Odds ratios were calculated to show the association between mutated genes and clinically-defined sAML or de novo AML. Clinical outcomes of interest were overall survival (OS) and cumulative incidence of relapse (CIR). Not only the established mutations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 but also ETV6 was significantly associated with clinically-defined sAML, which defined the molecular signature for st-MDS/AML and st-AML. No OS differences were observed between st-MDS/AML and st-AML. Molecularly-defined st-AML, now combined with st-MDS/AML cases, had considerably worse OS compared to ELN2022 favorable (5-yr OS 39.9%vs.70.4%;p<0.001) and intermediate risk (5-yr OS 39.9%vs.48.9;p=0.005) AML patients. MRD of secondary type mutations alone lacks predictive value, yet MRD of non-DTA mutations in CR is associated with increased CIR in st-AML (SHR MRDpos vs. MRDneg 3.25; p<0.001). Molecularly-defined st-AML, including st-MDS/AML, defines a distinct AML category with a unique genetic, clinical and treatment response profile, in which NGS-based MRD holds markedly prognostic significance.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018408
  2. Leukemia. 2026 Jan 14.
    Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia - a HARMONY study.
    Alberto Hernández-Sánchez, Ángela Villaverde Ramiro, Eric Sträng, Amin T Turki, María Abáigar, Jurjen Versluis, Ian Thomas, Marta Sobas, Javier Martínez Elicegui, Gastone Castellani, Axel Benner, Raúl Azibeiro, Jesse M Tettero, Rabea Mecklenbrauck, Joaquín Martínez-López, Marta Pratcorona, Ken I Mills, Guillermo Sanz, Maria Teresa Voso, Lehmann Sören, Christoph Röllig, Christian Thiede, Klaus H Metzeler, Konstanze Döhner, Michael Heuser, Torsten Haferlach, Peter Jm Valk, Nigel Russell, Jesús María Hernández-Rivas, Brian Huntly, Gert Ossenkoppele, Hartmut Döhner, Lars Bullinger.
      NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult NPM1-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in FLT3-ITD, DNMT3A, IDH1/IDH2, and TET2 genes, was applied to a training cohort of NPM1-mut AML patients included in clinical trials (n = 1001), an internal validation cohort more representative of real-world settings (n = 762), and an external validation cohort enrolled in UK-NCRI trials (n = 585). The HARMONY classification considered 51.8% of the NPM1-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; p < 0.001), thereby reclassifying 42.7% of NPM1-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the NPM1-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult NPM1-mut AML with potential clinical impact on allo-HSCT decision-making.
    DOI:  https://doi.org/10.1038/s41375-025-02851-9
  3. Blood Adv. 2026 Jan 15. pii: bloodadvances.2025018032. [Epub ahead of print]
    Stratifying Survival: The Role of Social Determinants of Health on AML Outcomes by ELN 2022 Criteria.
    Shai Shimony, Yating Wang, Angel M Cronin, Thomas P Walsh, Anne Charles, Natalie Slopen, Hae Lin Cho, Maximilian F Stahl, Rebecca P Bystrom, Marlise R Luskin, Gregory A Abel, Daniel J DeAngelo, Richard M Stone, R Coleman Lindsley, Andrew Hantel.
      Previous studies have demonstrated that social determinants of health (SDOH) are associated with overall survival (OS) in patients with acute myeloid leukemia (AML). Their interaction with the European LeukemiaNet (ELN) 2022 genetic risk criteria remains unclear. We evaluated the impact of SDOH, measured by the national Area Deprivation Index (nADI) and categorized as low (<=50; more advantaged) vs. high (>50; less advantaged), in 365 patients with newly diagnosed AML treated with intensive chemotherapy. Among ELN favorable (n=115) and adverse (n=166) risk groups, overall survival was similar for high and low nADI groups. Conversely, in intermediate risk patients (n=84), overall survival was higher for more advantaged patients (median 33 vs. 17 months, p=0.04), which persisted in multivariable analysis adjusted for age, race, sex, and hematopoietic cell transplantation as a time-varying covariate (HR 3.09, 95% confidence interval [CI] 1.3-7.34, p=0.01). In this intermediate risk group, response and transplantation rates did not differ by nADI group. Among patients consolidated with transplantation (59/84, 70%), survival was prolonged for more advantaged patients, although not significantly (2-year OS: 69% and 58%; p=0.069), which appeared to be mediated by a higher relapse rate (3-year cumulative incidence of 35% and 69%, p=0.06) rather than non-relapse mortality (20% and 19%, p=0.8). In conclusion, for patients with AML treated with intensive chemotherapy, more advantaged SDOH was associated with improved overall survival solely in the ELN intermediate risk group. This improvement appeared to be mediated by lower post-transplant relapse.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018032
  4. Leukemia. 2026 Jan 12.
    CHEK2 loss endows chemotherapy resistance to hematopoietic stem cells.
    Jing Zhou, Tianyuan Hu, Dian Li, Sanming Li, Minhua Li, Xiangguo Shi, Daisuke Nakada.
      Individuals with history of chemo- or radiotherapy frequently exhibit somatic mosaicism in the blood, often involving mutations in genes responsible for DNA damage responses (DDR), such as CHEK2. However, the mechanisms by which CHEK2 mutations promote the expansion of mutant cells following chemo- or radiotherapy remain poorly understood. Here, we demonstrate that loss of CHEK2 confers resistance to chemotherapy in hematopoietic stem and progenitor cells (HSPCs). Through a CRISPR-based screen, we identified CHEK2 as a gene whose loss enhances resistance to cytotoxic chemotherapies. A complementary drug screen revealed that CHEK2-mutant cells are also resistant to DNA hypomethylating agents. Chek2-deficient HSPCs persist in vivo following chemotherapy exposure and exhibit elevated levels of DNA damage compared to wild-type cells. Our findings establish that CHEK2 loss promotes chemoresistance in HSPCs, offering new insights into the role of CHEK2 in therapy-related clonal hematopoiesis observed in cancer patients.
    DOI:  https://doi.org/10.1038/s41375-025-02850-w
  5. Leukemia. 2026 Jan 12.
    Modulation of the clonal burden in patients with lower-risk myelodysplastic neoplasms treated with imetelstat.
    Valeria Santini, Amer M Zeidan, Koen Van Eygen, Pierre Fenaux, Ulrich Germing, Yazan F Madanat, Azra Raza, Michael R Savona, Mikkael A Sekeres, Sylvain Thépot, Marco G Raddi, Thomas Boyer, Libo Sun, Ying Wan, Tymara Berry, Qi Xia, Fei Huang, Souria Dougherty, Shyamala Navada, Faye Feller, Rami S Komrokji, Uwe Platzbecker.
      Existing treatments for lower-risk myelodysplastic syndromes/neoplasms (LR-MDS) focus on symptom relief. Until recently, altering the disease course was rarely considered a therapeutic objective. The first-in-class, direct, competitive telomerase inhibitor, imetelstat, demonstrated significantly higher rates of red blood cell (RBC) transfusion independence (TI) versus placebo in patients with non-del(5q), RBC transfusion-dependent LR-MDS who were relapsed/refractory to or ineligible for erythropoiesis-stimulating agents in the Phase 3 IMerge study (NCT02598661). In this exploratory analysis of IMerge, patients treated with imetelstat had greater sustained reductions in variant allele frequency of multiple mutations versus placebo recipients, which was positively associated with RBC-TI duration. Subsequent analyses showed that 70% of patients with a cytogenetic response with imetelstat achieved ≥1-year RBC-TI. Additionally, higher rates of ≥1-year RBC-TI were observed in patients with maximum variant allele frequency reduction of ≥50% in SF3B1 (58% vs. 7%), TET2 (90% vs. 9%), DNMT3A (100% vs. 13%), or ASXL1 (50% vs. 0%) and patients with ≥50% bone marrow ring sideroblast reduction (46% vs. 0%) versus patients who did not. Lastly, 60% of patients with ≥1-year RBC-TI had ≥50% reduction in telomerase activity/human telomerase reverse transcriptase RNA. These results suggest that imetelstat targets clonal progenitor cells and may modify LR-MDS biology.
    DOI:  https://doi.org/10.1038/s41375-025-02831-z
  6. Br J Haematol. 2026 Jan 14.
    Hypomethylating agents in vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS): A systematic review.
    Fieke W Hoff, Roochi Trikha, Emma M Groarke, Bhavisha A Patel.
      VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an X-linked, systemic, haemato-inflammatory syndrome caused by somatic mutations in the UBA1 gene. No standardized treatment guidelines exist, but evidence is emerging that treatment with hypomethylating agents (HMAs) can induce improvement of the inflammatory symptoms, reverse cytopenia, enable weaning of the corticosteroids and, in some cases, induce molecular remission. We systematically reviewed the literature to evaluate the experience with HMA in the management of VEXAS, following 2020 PRISMA guidelines across three databases. A total of 30 citations reporting 166 patients with genetically confirmed VEXAS syndrome treated with HMA were included. All but three patients were males (98%), and the median age was 71 years (range, 29-86). Inflammatory symptoms (96% of patients), constitutional symptoms (84%) and cytopenia (89%) were most frequently reported, and 81% had a concomitant diagnosis of myelodysplastic syndromes (MDS). Most mutations were substitutions of p.Met41 (81%). Overall inflammatory response was achieved in 59% of treated patients with most complete response (52%). Responses were documented in patients with and without concomitant MDS. Any haematological response was achieved in 74% of the patients, and eradication of the UBA1 clone (to a variant allele fraction of <2%) was detected in 51% of cases in whom mutation testing was performed (n = 32/63). Toxicity was the most frequent reason for discontinuation of therapy. This review highlights HMAs as a feasible option in the management of VEXAS syndrome. Prospective studies are needed to identify predictors for response or resistance and optimal regimens.
    Keywords:  UBA1; VEXAS; azacitidine; hypomethylating agent
    DOI:  https://doi.org/10.1111/bjh.70302
  7. Leukemia. 2026 Jan 12.
    Randomized phase 3 trial of Ropeginterferon alfa-2b versus surveillance after tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia (ENDURE/CML-IX).
    Andreas Burchert, Franck E Nicolini, Philipp le Coutre, Susanne Saussele, Andreas Hochhaus, Evin Tuere, Stephan K Metzelder, Kim Pauck, Holger Garn, Hartmann Raifer, Magdalena Huber, Norbert Gattermann, Martina Crysandt, Philippe Schafhausen, Matthias Bormann, Markus P Radsak, Agnès Guerci-Bresler, Thomas Illmer, Maria E Goebeler, Peter Herhaus, Lino L Teichmann, Georg-Nikolaus Franke, Fabian Lang, Stefan W Krause, Robert Möhle, Martine Klausmann, Frank Stegelmann, Christoph Lutz, Gabriel Etienne, Andrea Stoltefuß, Joachim R Göthert, Thomas Ernst, Maisun Abu-Samra, Heinz-Gert Höffkes, Andreas Neubauer, Ying Wang, Paul Weiland, Clara Otto, Lea Kiessler, Theresa Weber, Lea Kroning, Andrea Nist, Thorsten Stiewe, Rüdiger Hehlmann, Behnaz Aminossadati, Michael Wittenberg, Kerstin Winterstein, Thomas Oellerich, Marcus Lechner, Markus Pfirrmann, Carmen Schade-Brittinger, Paul Klemm, Christian Michel.
      Treatment-free remission (TFR) after discontinuation of ABL tyrosine kinase inhibitors (TKIs) is an important therapeutic goal in chronic myeloid leukemia (CML). Interferon-α (IFN) has been suggested to promote durable TFR. The phase 3 ENDURE trial (NCT03117816; EUDRA-CT 2016-001030-94) prospectively tested this hypothesis in patients with stable deep molecular remission after TKI therapy. A total of 203 patients were randomised 1:1 to receive ropeginterferon alfa-2b (ropeg-IFN; 100 µg subcutaneously every two weeks for 15 months, n = 95) or observation alone (n = 108) after TKI discontinuation. The primary endpoint was molecular relapse-free survival (MRFS), defined as time to loss of major molecular response (MMR) or death. At a median follow-up of 36 months, 25-month MRFS was 56% (95% confidence interval (CI), 45-66) with ropeg-IFN and 59% (95% CI, 49-68) with observation (hazard ratio (HR), 1.02; 95% CI, 0.68-1.55; P = 0.91). Among 83 patients with molecular data after TKI restart, 79 (95%) regained at least MMR, 78 within 12 months (median 3 months, interquartile range: 2-4 months). Ropeg-IFN was well tolerated (median administered dose of 92 µg, range 3-104), and no new safety signals were observed. Ropeg-IFN maintenance did not improve the probability of sustained TFR after TKI discontinuation.
    DOI:  https://doi.org/10.1038/s41375-025-02859-1
  8. Blood Neoplasia. 2026 Feb;3(1): 100178
    Dual FLT3/PIM inhibitor dapolsertib in acute myeloid leukemia: results from the phase 1/2 DIAMOND-01 trial.
    Giovanni Martinelli, Scott R Solomon, Sudipto Mukherjee, Armando Santoro, Stephen A Strickland, Susana Vives, Farhad Ravandi, Roland B Walter, Rachel J Cook, Ewa Lech-Maranda, Maria Calbacho, Agnieszka Wierzbowska, Giovanni Marconi, Evelyn Acuña-Cruz, Isabel Cano-Ferri, Francesco Bertolini, Tomasz Rzymski, Alessandro Paoli, Giovanni Marino Merlo, Faten Koraichi Auriol, Sonia Zicari, Antonio Galleu, Ira Gupta, Pau Montesinos.
      Acute myeloid leukemia (AML) is an aggressive hematopoietic cancer with poor survival outcomes. Despite improvements with recent FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance is common, and responses are short. Dapolsertib (MEN1703) is a novel, first-in-class dual inhibitor of PIM (proviral integration site for Moloney murine leukemia virus) and FLT3 kinases, with activity in both FLT3-mutated and wild-type cells. A phase 1/2 open-label, multicenter, dose-escalation study (DIAMOND-01) investigated the maximum tolerated dose (MTD) of single-agent dapolsertib and assessed its safety, efficacy, pharmacokinetic (PK) profile, pharmacodynamic biomarkers, and genomics in patients with AML with no standard therapeutic options available. Seventy-three patients received oral doses of dapolsertib ranging from 25 to 150 mg per day (14 consecutive days over 21-day cycles). In the dose-escalation phase, the MTD was 125 mg and was selected for dose expansion. The most common grade ≥3 adverse events in patients receiving 125 mg were pneumonia (38%), thrombocytopenia (30%), and anemia (27%); most of these events were deemed not treatment related. For patients receiving 125 mg dapolsertib (n = 55), the overall response rate was 9%, with a median 2.07-month duration of response, and 4 of 5 responses were observed in patients with isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations. PK analysis indicated rapid absorption of oral dapolsertib, an elimination half-life suitable for once daily dosing and a PK independent of formulation and IDH mutational status. Pharmacodynamic activity was confirmed in 50% of evaluable patients. Overall, dapolsertib demonstrated modest single-agent activity in patients with AML. This trial was registered at www.clinicaltrials.gov as #NCT03008187.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100178
  9. Cell Stem Cell. 2026 Jan 13. pii: S1934-5909(25)00452-7. [Epub ahead of print]
    Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness.
    James Bartram, Sydney Treichel, Baobao Annie Song, Juying Xu, Devyani Sharma, Waseem Nasr, Madeline Frangiosa, Andrew Harley, Travis Nemkov, Angelo D'Alessandro, Nathan Salomonis, H Leighton Grimes, Marie-Dominique Filippi.
      Adult hematopoietic stem cells (HSCs) sustain the lifelong production of all mature blood and immune cells. HSCs possess extensive regenerative potential, but their self-renewal is limited. A long-standing question has been why replicative history negatively impacts HSC functions. We found that accrued divisions alter HSC production, generating low-output bone-marrow landscapes that are highly variable in lineage contribution and transcriptionally divergent within individual lineages. Division-driven HSC functional alterations arise from redirecting branched-chain amino acid (BCAA) usage from catabolic toward anabolic activity, causing faster HSC cell-cycle kinetics. Adding a BCAA transamination product overcomes the BCAA catabolic checkpoint and slows down the cell cycle, durably rescuing balanced lineage output of HSCs with accrued divisions. Hence, our study suggests the paradigm whereby replicative history causes metabolic and transcriptional drift, generating divergent HSC output. Division-dependent HSC functional drift can be restored by metabolite replacement, which has long-term therapeutic implications for HSC regenerative medicine.
    Keywords:  branch chain amino acid catabolism; hematopoietic stem cells; metabolism; self-renewal
    DOI:  https://doi.org/10.1016/j.stem.2025.12.018
  10. Blood. 2026 Jan 12. pii: blood.2024028031. [Epub ahead of print]
    Compartmentalized inflammatory landscape and macrophage plasticity regulate Tet2+/- mediated clonal hematopoiesis.
    Kevin Lee, Cih-Li Hong, Wimeth Dissanayake, Gulzada Kulzhanova, Alexander Noel Pfeffer, Haiyin Li, Senthil Sivakumar, Zi Yin, Emily R Quarato, Lauren Benoodt, Jeevisha Bajaj, Chike Cao, Chia-Lung Wu, Laura M Calvi, Shu-Chi Allison Yeh.
      Clonal hematopoiesis of indeterminate potential (CHIP) is driven by hematopoietic stem cells (HSCs) carrying leukemia-associated mutations that expand in the bone marrow. Several prior studies have revealed that the spatial organization of hematopoietic cells in the bone marrow impacts clonal behaviors. Specifically, leukemic blasts have been found to expand almost exclusively in a subset of marrow cavities that are undergoing active bone remodeling, but whether these cavities also support the expansion of non-malignant mutant clones has never been visualized. Although it is widely appreciated that systemic inflammation promotes the selection of mutant clones, this view has emerged without considering the potential heterogeneity in the inflammatory landscape shaped by local bone remodeling. Leveraging intravital imaging and a murine model of CHIP (Tet2+/-), we demonstrated transcriptional and functional compartmentalization of the marrow microenvironment. Macrophages within non-resorptive cavities are inherently anti-inflammatory, which suppresses disease-initiating Tet2+/- cells while preserving the healthy counterpart. Time-lapse imaging further revealed non-transient association between Tet2+/- clones and CD206+ macrophages. Spatially resolved single-cell transcriptomic profiling and functional assessment revealed that physiological bone remodeling influences CD206+ macrophage plasticity and cytokine secretion which regulate the clonal burden. Additionally, anti-tumor immunity alteration within the microenvironment occurred as early as the formation of initial clones. Suppressing bone remodeling with zoledronate or targeting macrophage-associated niche factors mitigated clonal development. Collectively, our study reveals a previously unrecognized inflammatory landscape shaped by local bone remodeling. The finding presents targetable mechanisms and warrants further studies on the use and precautions of bone-modulating management in clonal blood disorders.
    DOI:  https://doi.org/10.1182/blood.2024028031
  11. Leukemia. 2026 Jan 16.
    Characteristics and prognostic significance of myelodysplasia-related features in VEXAS syndrome.
    FRENVEX group
      
    DOI:  https://doi.org/10.1038/s41375-025-02858-2
  12. Leukemia. 2026 Jan 16.
    CSF1R marks a subset of foetal haematopoietic multipotent progenitor cells with acute myeloid leukaemia propagation properties.
    Giuseppina Camiolo, Daniel González Silvera, Tom Leah, Jürg Schwaller, Katrin Ottersbach.
      KMT2A-rearranged infant leukaemia is one of the most severe malignancies in infants and children, and is characterised by a very aggressive phenotype and lineage plasticity. KMT2A::MLLT3 is among the most common translocations initiating leukaemia in infants, where it can manifest with a myeloid or lymphoid leukaemia phenotype. The cell-of-origin and the mechanisms driving lineage choice in KMT2A::MLLT3+ infant leukaemia are poorly understood. In this study, we show that a subset of foetal lymphoid-primed multipotent progenitors (LMPPs) expressing the Colony-Stimulating Factor 1 receptor (CSF1R) gives rise to acute myeloid leukaemia (AML) upon KMT2A::MLLT3 induction in a mouse model, with the myeloid phenotype, at least in part, being dependent on CSF1R signalling. In line with their leukaemia-propagating properties, KMT2A::MLLT3 + CSF1R+ LMPPs possess a stem cell-like and myeloid-biased expression signature and require autophagy to expand and form blast-like colonies in methylcellulose. Interrogation of public datasets confirms the existence of a human foetal-restricted CSF1R+ LMPP population at early stages of embryonic development. Finally, CSF1R inhibition on a KMT2A::MLLT3+ paediatric leukaemia cell line resulted in significant cell death, suggesting that CSF1R could be therapeutically targeted in these patients. Our findings suggest that KMT2A::MLLT3+ infant AML may originate from foetal liver CSF1R+ LMPPs, and that these patients may benefit from anti-CSF1R-CAR-T cell therapy.
    DOI:  https://doi.org/10.1038/s41375-025-02856-4
  13. Haematologica. 2026 Jan 15.
    First-line tagraxofusp leads to durable responses and prolonged survival in adults with blastic plasmacytoid dendritic cell neoplasm regardless of fitness level.
    Naveen Pemmaraju, Marco Herling, Kendra L Sweet, Anthony S Stein, Sumithira Vasu, Todd L Rosenblat, David A Rizzieri, Cristina Papayannidis, Eunice S Wang, Marina Konopleva, Michael Zuurman, Alessandra Tosolini, Muzaffar Qazilbash, Andrew A Lane.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.300036
  14. Hemasphere. 2026 Jan;10(1): e70282
    Drivers of clinical resistance to venetoclax and hypomethylating agents in acute myeloid leukemia and strategies for improving efficacy.
    Ida Vänttinen, Joseph Saad, Tanja Ruokoranta, Sari Kytölä, Guangrong Qin, Bahar Tercan, Pia Ettala, Anu Partanen, Marja Pyörälä, Johanna Rimpiläinen, Timo Siitonen, Mikko Manninen, Peter J M Valk, Gerwin Huls, Vésteinn Thorsson, Caroline A Heckman, Mika Kontro, Heikki Kuusanmäki.
      The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with hypomethylating agents (HMAs) has improved treatment outcomes for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy and is increasingly used in the relapsed/refractory setting. However, primary resistance remains a significant challenge, affecting 20%-35% of treatment-naïve and around 50% of previously treated AML patients. To investigate the mechanisms driving primary resistance to VEN-HMA therapy, we analyzed genetic, transcriptomic, BCL-2 family protein expression, and ex vivo drug sensitivity data from 101 AML patients and correlated these profiles with clinical outcomes to VEN-HMA. Our study found that blasts from refractory patients exhibit an elevated BCL-XL/BCL-2 protein expression ratio, an immature CD34+CD38- phenotype, and frequent TP53 mutations. Consistent with the high ratio of BCL-XL/BCL-2, resistant samples showed increased ex vivo sensitivity to the dual BCL-2/BCL-XL inhibitor navitoclax. In addition, SMAC mimetics were effective in refractory blasts, which correlated with high TNF gene expression in these cells. Ex vivo treatment with the combination of navitoclax and SMAC mimetics further enhanced the eradication of VEN-HMA refractory blasts, although toxicity was also observed in healthy CD34+ cells. In conclusion, our integrative analysis identifies molecular signatures associated with primary VEN-HMA resistance and highlights BCL-2/BCL-XL inhibition and SMAC mimetics as therapeutic strategies to target resistance.
    DOI:  https://doi.org/10.1002/hem3.70282
  15. iScience. 2026 Jan 16. 29(1): 114289
    Integrative spatial multi-omics reveal niche-specific inflammatory signaling and differentiation hierarchies in AML.
    Enes Dasdemir, Ivo Veletic, Christopher P Ly, Andres E Quesada, Christopher D Pacheco, Fatima Z Jelloul, Pamella Borges, Sreyashi Basu, Sonali Jindal, Zhiqiang Wang, Alexander Lazar, Khalida M Wani, Dinler A Antunes, Patrick K Reville, Preethi H Gunaratne, Robert J Tower, Padmanee Sharma, Hussein A Abbas.
      Acute myeloid leukemia (AML) is a clonal disorder characterized by immature blasts and arrested differentiation that primarily affects the bone marrow (BM) and occasionally presents as extramedullary (EM) disease. EM manifestations highlight AML's adaptability to distinct microenvironments, which we examined using spatial analyses of medullary and EM tissues. We describe a workflow for Visium-based spatial transcriptomics in medullary and EM AML, revealing insights into cell-cell communication and the spatial organization of AML hierarchies. In BM, monocytes and granulocyte-monocyte progenitors colocalized with leukemic populations, sharing molecular signatures with those in EM sample. CXCL12-CXCR4-mediated communication correlated with PI3K/AKT/mTOR signaling in inflammatory niches. Trans-differentiation signals concentrated in AML-infiltrated regions; committed-like AML cells resided in inflammatory niches distant from trabeculae, while primitive-like cells localized near the endosteal niche. GeoMX digital spatial profiling and Opal multiplex fluorescent immunohistochemistry provided orthogonal validation. Overall, our study offers a valuable multimodal resource for exploring AML spatial biology with potential applications in other BM malignancies.
    Keywords:  Components of the immune system; Proteomics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.114289
  16. Am J Hematol. 2026 Jan 14.
    A Murine Bispecific Antibody Efficiently Redirects T Cells Against Calr Mutated Stem Cells In Vivo.
    Shengen Xiong, Tamara Wais, Cecilia Varga, Christina Schueller, Sarada Achyutuni, Robert Kralovics.
      Calreticulin (CALR) mutations are prevalent in 20%-30% of patients with BCR::ABL1-negative myeloproliferative neoplasms (MPN). Mutant calreticulin (mutCALR), presented by the thrombopoietin receptor (MPL, also known as TPOR or CD110) on the surface of the disease-initiating MPN progenitors, represents an ideal target for curative immunotherapies including monoclonal antibodies, bispecific T cell engaging antibodies (TCE), and CAR-T cell therapies. Despite that two clinical TCE candidates have advanced into phase 1 trials in recent 2 years, depletion of mutCALR+ hematopoietic stem cells and normalization of hematopoiesis remained absent in preclinical evaluation. Here, we developed a bispecific T cell engager DX1-2C11 that specifically and efficiently eradicates mutCALR-expressing cells via recruiting polyclonal T cells. DX1-2C11 depleted Ba/F3 cells expressing mutCALR, as well as primary murine myeloid cells in a dose-dependent manner in vitro. In CALRdel52 transgenic mice, a single dose of DX1-2C11 activated CD4+ and CD8+ T cells in the peripheral blood, spleen and bone marrow within 24 h. Furthermore, a single dose of DX1-2C11 reduced platelet counts in the periphery and decreased mutant stem/progenitor cell populations in the spleen and bone marrow by Day 7 posttreatment. Notably, the reduction of mutant burden was durably maintained in secondary recipient mice. In the disseminated NSG model, DX1-2C11 delivered immediate tumor burden reduction and significantly prolonged the overall survival of mice compared to the control group. Taken together, these data suggest that bispecific T cell engaging antibody targeting mutCALR represents a curative strategy that efficiently eliminates mutant MPN stem cells in vivo.
    DOI:  https://doi.org/10.1002/ajh.70206
  17. bioRxiv. 2026 Jan 08. pii: 2026.01.08.697228. [Epub ahead of print]
    MYST acetyltransferases are a targetable therapeutic vulnerability in SETBP1-mutant leukemia.
    Hanqian L Carlson, Thai T Nguyen, Samantha Tauchmann, Sarah A Carratt, Traci L Kruer, Nana Adjoa Ben-Crentsil, Maria Balasis, Hyeyoon Kim, Chia-Feng Tsai, Tao Liu, Shawn B Shrestha, Jared M Fischer, Eric Padron, Theodore P Braun, Julia E Maxson.
      Mutations in SET binding protein 1 ( SETBP1 ) are associated with an adverse prognosis in myeloid malignancies. These mutations stabilize SETBP1 protein, driving increased expression of a progenitor-associated gene expression program through incompletely described mechanisms. A proteomic screen revealed interactions between SETBP1 and members of the MYST acetyltransferase complexes, including the catalytic subunits-KAT6A and KAT7. Mutant SETBP1 increases the localization of MYST complexes at known SETBP1 target genes, including the Hoxa cluster, where it drives increased histone acetylation and gene expression. Treatment of SETBP1 D868N -expressing myeloid progenitors with MYST inhibitors reduced target gene expression. To establish the efficacy of MYST inhibition in vivo , we treated mice harboring a syngeneic SETBP1 -mutant leukemia with the clinical-grade MYST inhibitor-PF-9363. This resulted in complete hematologic control and increased survival. MYST inhibition was also highly effective against a SETBP1 -mutant PDX model. These studies identify MYST acetyltransferases as promising therapeutic targets in SETBP1 -mutant malignancies.
    Statement of Significance: SETBP1 mutations are markers of high-risk myeloid malignancies, but we lack any targeted therapies to improve outcomes. In this study, we identify MYST acetyltransferases as key drivers of mutant SETBP1-driven transcription. MYST inhibitors are highly effective against SETBP1-mutant leukemia and represent a promising avenue for clinical translation.
    DOI:  https://doi.org/10.64898/2026.01.08.697228
  18. J Clin Invest. 2026 Jan 16. pii: e193636. [Epub ahead of print]136(2):
    FBXO11 suppression rewires an NPM1-centered interactome influencing the progression of myelodysplastic syndrome.
    Madeline Niederkorn, Lavanya Bezavada, Anitria Cotton, Lance E Palmer, Lahiri Konada, Trent Hall, Vishwajeeth R Pagala, Jinbin Zhai, Zuo-Fei Yuan, Yingxue Fu, Jacob A Steele, Shilpa Narina, Andrew Schild, Chengzhou Wu, Sarah Aminov, Michael Schieber, Erin McGovern, Aaron B Taylor, Sandeep Gurbuxani, Peng Xu, Peng Ji, Laura J Janke, Anthony A High, Guolian Kang, Shondra M Pruett-Miller, Mitchell Weiss, Amit Verma, Raajit K Rampal, John D Crispino.
      Myelodysplastic syndromes (MDSs) are malignant hematopoietic stem and progenitor cell (HSPC) disorders that lead to ineffective blood production with poor outcomes. We previously showed that F-box only protein 11 (FBXO11) is downregulated in MDS, and here we report how this event contributes to disease progression. Integration of multiomics data revealed that the SCF-FBXO11 complex regulates spliceosome and ribosome components in a nucleophosmin 1 (NPM1)-centric network. FBXO11 facilitates the ubiquitylation of NPM1, whereby deletion of FBXO11 results in the reorganization of NPM1 and a de-repression of alternative splicing. Label-free total quantitative proteomics demonstrated that the FBXO11-NPM1 interactome was markedly downregulated in cells from patients with CD34+ MDS. In addition, we discovered that MYC was evicted from the FBXO11 promoter by TLR2 activation, revealing that it was a MYC target gene and explaining why FBXO11 expression was decreased in MDS. In MDS mouse models, genetic ablation of Fbxo11 exacerbated neutropenia concomitant with a profound decrease in NPM1 protein levels. Finally, we discovered rare mutations in FBXO11, which mapped to a previously unstudied functional intrinsically disordered region (IDR) in the N-terminus responsible for binding NPM1. These data support a model in which FBXO11 rewires RNA binding and ribosomal subnetworks through ubiquitylation of NPM1, ultimately restricting MDS progression.
    Keywords:  Hematology; Leukemias; Oncology; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/JCI193636
  19. Blood Adv. 2026 Jan 15. pii: bloodadvances.2025016879. [Epub ahead of print]
    Antileukemic therapies for older adults with AML ineligible for conventional therapy: systematic review & meta-analysis.
    Maria Jose Oliveros, Saifur R Chowdhury, Yetiani Roldan, Sara Ibrahim, Gonzalo Bravo-Soto, Charles E Foucar, Gurleen Bhogal, Barbara Burgos-Mansilla, Mobina Bagherianlemraski, Hamed Movahed, Ruvistay Gutierrez-Arias, Tanin Khorrami Taj, Yaping Chang, Sayed Kaveh Hadeiy, Roberta Demichelis-Gómez, Luca Malcovati, Kah Poh Loh, Uwe Platzbecker, Linda Gilberto, John Treitz, Maria R Baer, Bernard Lawrence Marini, Ryan J Mattison, Mikkael A Sekeres, Romina Brignardello-Petersen.
      Older adults with newly diagnosed acute myeloid leukemia (AML) are often ineligible for conventional "7+3" induction chemotherapy. Despite recent drug approvals, treatment outcomes remain poor in this population. We conducted an updated systematic review to inform the 2025 American Society of Hematology (ASH) AML update guidelines in older adults. This review compared the efficacy and safety of low-dose cytarabine (LDAC), azacitidine (AZA), 5- and 10-day decitabine (DEC), and gemtuzumab ozogamicin, alone or combined with drugs such as venetoclax (VEN), in older adults with AML ineligible for conventional chemotherapy. We included randomized controlled trials (RCTs) and non-randomized studies (NRS) of adults aged ≥55 years with AML, and synthesized evidence on mortality, remission, quality of life (QoL), functional status, and severe toxicity. We applied GRADE to assess the certainty of evidence. We included 47 studies (30 RCTs, 17 NRS). AZA or LDAC combined with VEN probably reduces mortality and improves remission and QoL. AZA plus isocitrate dehydrogenase-1 (IDH1) inhibitors may reduce 1-year mortality and improve remission and survival in patients with IDH1-mutated AML. Compared with DEC alone, combining DEC with other agents showed inconsistent effects with mostly low certainty of conclusions. VEN combinations showed promising effects on mortality and remission but lacked data on QoL and functional status. In older adults with AML ineligible for conventional therapy, evidence suggests that hypomethylating agents (HMAs) or LDAC combined with VEN likely improves survival and remission outcomes. Treatment decisions should consider patient goals and functional status. These findings informed eight recommendations in updated ASH-AML guidelines.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016879
  20. Genome Biol. 2026 Jan 16.
    An inflammatory and quiescent HSC subpopulation expands with age in humans.
    Ksenia R Safina, Basit Salik, Dylan Kotliar, Michelle Curtis, Jonathan D Good, Chen Weng, Shawn David, Soumya Raychaudhuri, Antonia Kreso, Jennifer J Trowbridge, Vijay G Sankaran, Peter van Galen.
      Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map reveals previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NFκB, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.
    DOI:  https://doi.org/10.1186/s13059-026-03936-z
  21. Exp Hematol. 2026 Jan 12. pii: S0301-472X(26)00012-3. [Epub ahead of print] 105379
    Evaluation of dual BCL-2/BCL-XL inhibition in AML preclinical models with and without prior venetoclax therapy.
    Reecha Shah, Nathan Kingston, Giulia Fabbri, Jamal Saeh, Courtney Andersen, Patricia Cheung.
      Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy that relies heavily on the anti-apoptotic protein B-cell lymphoma 2 (BCL-2) for survival.1 Venetoclax, a BCL-2 inhibitor, exploits this dependency and is currently approved for treatment of elderly AML patients. BCL-XL, another pro-survival protein in the BCL-2 family, has been identified as a key driver of both intrinsic and acquired resistance to venetoclax.2 Patients often develop resistance to BCL-2 inhibition through upregulation of BCL-XL.3 This study investigates the efficacy of a dual BCL-2/BCL-XL inhibitor and its combination with standard-of-care (SOC) agents. Dual BCL-2/BCL-XL inhibitor demonstrates robust activity in AML cell lines and patient-derived models, including activity in samples from patients who relapsed following venetoclax therapy. Its combination with SOC agents deepens the anti-leukemic activity both in vitro and in vivo. Among the combination regimens tested, cytarabine or hypomethylating agents (HMA) drive strong blast reduction in patient samples previously exposed to venetoclax and yield improved survival in AML patient-derived xenograft models with prior venetoclax/5-azacytidine treatment. These preclinical findings support the clinical evaluation of dual BCL-2/BCL-XL inhibition in AML patients, particularly, those who do not respond to venetoclax.
    Keywords:  AZD0466; Acute Myeloid Leukemia; Apoptosis; BCL-2/BCL-XL inhibitor; BH3 mimetic; Combination Treatment; Targeted therapy
    DOI:  https://doi.org/10.1016/j.exphem.2026.105379
  22. Leukemia. 2026 Jan 12.
    Modeling donor age and type trade-offs for personalized selection in allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide prophylaxis.
    Rohtesh S Mehta, Yosra M Aljawai, Partow Kebriaei, Gabriela Rondon, Warren Fingrut, Portia Smallbone, Betul Oran, Amanda Olson, Richard E Champlin, Elizabeth J Shpall.
      The prevailing fixed-hierarchy approach to donor selection for allogeneic hematopoietic cell transplantation (HCT) fails to capture critical interactions between donor age and type. We addressed this by analyzing 1713 adult recipients of matched related (MRD), matched unrelated (MUD), or haploidentical donors, receiving post-transplantation cyclophosphamide, using both regularized-Cox and XGBoost machine learning models. Our analysis revealed that the overall, independent association of donor age with survival was modest; however, its importance became pivotal within specific, context-dependent trade-offs. For example, while age-matched MRD and MUD were equivalent, a younger MUD was superior to an older MRD for elderly recipients. The survival advantage of MUD over haploidentical donors was consistent and magnified with increasing recipient age. We identified a non-linear relationship between baseline risk and the benefit of a matched versus a haploidentical donor; with the gain being maximal for intermediate-risk patients but attenuated in the highest-risk stratum. Our framework quantifies the gap that persists even between HLA-favorable haploidentical donors and matched donors. These findings provide a quantitative framework -the principles of which we have made explorable via an interactive web application -for a personalized, risk-adapted approach to donor selection. The clinical utility of this model must be confirmed in future validation studies.
    DOI:  https://doi.org/10.1038/s41375-025-02857-3
  23. Lancet. 2026 Jan 08. pii: S0140-6736(25)02164-6. [Epub ahead of print]
    VEXAS syndrome: a comprehensive review of pathogenesis, clinical spectrum, and therapeutic strategies.
    Emma M Groarke, Benjamin Turturice, Bhavisha A Patel, Kaitlin A Quinn, Alice Fike, Peter C Grayson.
      Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a monogenic disease of adulthood characterised by treatment-refractory systemic inflammation and progressive bone marrow failure. VEXAS syndrome is caused by acquired mutations in the UBA1 gene that are restricted to haematopoietic cells. Men aged 50 years or older are particularly susceptible to VEXAS syndrome, with prevalence estimates of approximately one in 4000 men. Perturbation of UBA1, the master enzyme of cellular ubiquitination, promotes myeloid-driven inflammation that is difficult to control with medications other than glucocorticoids. Cytokine-directed therapies (ie, IL-6 and JAK inhibitors) might temporise symptoms and allow glucocorticoid reduction. Hypomethylating agents (ie, azacytidine) can induce clinical and molecular remission in some patients, but are associated with substantial toxicities. Haematopoietic cell transplant might be effective treatment in patients who are suitable candidates. The discovery of VEXAS syndrome highlights the potential role of somatic mutations in complex inflammatory diseases.
    DOI:  https://doi.org/10.1016/S0140-6736(25)02164-6
  24. Blood. 2026 Jan 15. pii: blood.2025030760. [Epub ahead of print]
    PU.1-Activated Genomic Regions Define Low-risk MDS Subsets Characterized by Immune Dysregulation and Disease Progression.
    Veronica Vallelonga, Francesco Gandolfi, Matteo Zampini, Elena Riva, Giulia Maggioni, Denise Ventura, Elena Saba, Alberto Termanini, Sara Polletti, Elena Prosperini, Laura Crisafulli, Alessia Campagna, Ivan Ferrari, Nicole Pinocchio, Gabriele Todisco, Silvia Pedretti, Michela Calvi, Clara Di Vito, Domenico Mavilio, Nico Mitro, Francesca Ficara, Matteo G Della Porta, Serena Maria Luisa Ghisletti.
      Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms with an increased risk of progression to secondary acute myeloid leukemia (sAML). This study investigates the genomic correlates of disease progression in MDS by profiling active genomic regulatory regions and their transcriptional impact through H3K27ac ChIP-seq and RNA-seq analysis on CD34+ bone marrow progenitors cells isolated from a prospective cohort of 86 and 357 patients, respectively. Our analysis revealed distinct patterns of genomic region activation and transcriptional regulation across different disease stages (low-risk MDS, high-risk MDS and sAML). Unexpectedly, unsupervised clustering revealed a subset of low-risk MDS patients displaying regulatory and transcriptional profiles similar to those of high-risk MDS and sAML, highlighting early molecular events that may predispose patients to disease progression. This subset is characterized by PU.1 genomic occupancy in regions linked to immune and inflammatory responses, increased T-cell and NK activation, and a higher frequency of SRSF2 mutations. Clinically, patients in this group exhibit greater susceptibility to infections and cardiovascular events, along with an elevated risk of disease progression, resulting in a significantly reduced overall survival. Functional studies demonstrate that PU.1 inhibition suppresses MDS cell proliferation and clonogenicity, as impaired PU.1 binding inhibits the activation of key transcriptional programs involved in disease advancement. Collectively, these findings identify epigenetic factors that predispose low-risk MDS patients to progression into high-risk MDS and, ultimately, sAML.
    DOI:  https://doi.org/10.1182/blood.2025030760
  25. JCO Oncol Pract. 2026 Jan 13. OP2500675
    Re-Evaluating Donor Selection Priorities for Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide.
    Rohtesh S Mehta, Yosra M Aljawai, Partow Kebriaei, Chitra Hosing, Amanda Olson, Betul Oran, Uday Popat, Gabriela Rondon, Katayoun Rezvani, Richard E Champlin, Elizabeth J Shpall.
       PURPOSE: The prognostic significance of traditional donor selection criteria for human leukocyte antigen (HLA)-matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) is uncertain in the era of post-transplant cyclophosphamide (PTCy). We re-evaluated the impact of donor age, sex, cytomegalovirus (CMV) serostatus, and ABO compatibility in a large, contemporary cohort of patients receiving PTCy-based graft-versus-host disease (GVHD) prophylaxis.
    METHODS: We retrospectively analyzed 699 patients who underwent an 8/8 HLA-matched MUD HCT with PTCy. We assessed the impact of donor characteristics on overall survival (OS), progression-free survival (PFS), relapse, nonrelapse mortality, GVHD, and engraftment. Least absolute shrinkage and selection operator regression confirmed variable selection.
    RESULTS: Recipient-related factors, specifically the disease risk index and HCT-comorbidity index, were the primary determinants of OS and PFS. By contrast, traditional donor characteristics had a limited impact on survival. Donor age, analyzed as a continuous variable, was not associated with OS (hazard ratio [HR], 0.99 [95% CI, 0.978 to 1.011]; P = .524). Similarly, donor CMV and ABO compatibility did not influence survival. The effect of donor-recipient sex mismatch was primarily limited to modulating GVHD risk. Female-to-male sex mismatch had higher hazard for grade 3-4 acute GVHD (aGVHD) (HR, 3.08 [95% CI, 1.15 to 8.20]; P = .025; adjusted P = .222), whereas male-to-female grafts were associated with a 42% reduction in the hazard for grade 2-4 aGVHD (95% CI, 0.39 to 0.87; P = .009; adjusted P = .045). Major ABO mismatch was associated with delayed neutrophil engraftment in bone marrow grafts but not in peripheral blood grafts.
    CONCLUSION: Collectively, these findings suggest that for patients receiving PTCy, the hierarchy of donor selection factors might have evolved, allowing for greater flexibility in donor choice. Our findings provide a solid foundation for future larger external validation studies.
    DOI:  https://doi.org/10.1200/OP-25-00675
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒18 at 5:59.