bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–10–12
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. MECOM is a master repressor of myeloid differentiation through dose control of CEBPA in acute myeloid leukemia.
  2. Combining drugs that bypass p53 to treat TP53-mutated leukemias.
  3. Mutation profiling of chronic myeloproliferative neoplasms: improving clinical-molecular prognostic models.
  4. CD123 expression and its correlation with mutation profile in acute myeloid leukaemia.
  5. Genetic and epigenetic alterations at secondary resistance after continued decitabine-based treatment of acute myeloid leukemia in the randomized phase II DECIDER trial.
  6. FLT3-ITD measurable residual disease from the QuANTUM-First trial.
  7. Applicability of current prognostication models for MDS patients with DDX41 mutation.
  8. Matched Unrelated vs Haploidentical Donor Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.
  9. Comparison of the clinicopathological features in myeloproliferative or myelodysplastic neoplasms with SF3B1/JAK2, SF3B1/CALR, or SF3B1/MPL co-mutations.
  10. Clinical outcomes of allogeneic cell transplantation for patients with chronic myeloid leukemia.
  11. Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations.
  12. A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.
  13. Transplantation in lower risk MDS patients: a prospective phase 2 trial based on donor availability.
  14. The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia.
  15. Allogeneic stem cell transplantation in chronic myelomonocytic leukemia: analysis of post-transplant survival and risk factors in 138 Mayo Clinic patients.
  16. Pretransplant MRD and chemotherapy in AML: A transplant physician's perspective.
  17. Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche.
  18. Assessing drivers of disparate outcomes and applicability of risk stratification in a cohort of patients with myelofibrosis.
  19. Clinical and biological predictors of treatment-free remission in CML.
  20. Germline LCP1 mutations cause immunodeficiency with neutropenia, monocytopenia, lymphopenia and defective cytokinesis.
  21. The immunotherapy landscape in AML: Defining knowledge gaps toward rational combinatorial strategies.
  22. Heart failure in patients with acute myeloid leukemia (AML) treated with anthracycline agents during remission induction therapy: a systematic review and meta-analysis.
  23. Phase I Study of Rogocekib in Patients with Relapsed or Refractory Hematologic Malignancies.
  1. Blood. 2025 Oct 08. pii: blood.2025028914. [Epub ahead of print]
    MECOM is a master repressor of myeloid differentiation through dose control of CEBPA in acute myeloid leukemia.
    Dorien Pastoors, Marije Havermans, Roger Mulet-Lazaro, Leonie Smeenk, Sophie Ottema, Claudia A J Erpelinck-Verschueren, Stanley van Herk, Maikel Anthonissen, Tim Grob, Shruthi Subramanian, Julie A I Thoms, John E Pimanda, Bas J Wouters, Berna H Beverloo, Torsten Haferlach, Claudia Haferlach, Johannes Zuber, Eric Bindels, Ruud Delwel.
      The transcription factor MECOM, located at 3q26, is essential for hematopoietic stem cells (HSCs) in healthy individuals. Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in one of the most aggressive subtypes of acute myeloid leukemia (AML). Aberrantly expressed MECOM is essential for the survival and immature phenotype of these leukemia cells. Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of CEBPA, encoding a transcription factor required for neutrophil development which is frequently mutated in other AML subtypes. MECOM depletion is accompanied by a severe loss of CD34 and gain of mature myeloid cell surface marker CD15. MECOM exerts its inhibitory effect on differentiation by binding to the +42kb CEBPA enhancer. This is partially dependent on the interaction between MECOM and its co-repressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, AML patients with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA levels. Our study directly connects two major players in normal and malignant hematopoiesis, MECOM and CEBPA, and unveils how MECOM maintains self-renewal by repressing CEBPA-induced differentiation.
    DOI:  https://doi.org/10.1182/blood.2025028914
  2. Blood Adv. 2025 Oct 08. pii: bloodadvances.2025016683. [Epub ahead of print]
    Combining drugs that bypass p53 to treat TP53-mutated leukemias.
    Sudipta Biswas, Zeinab Zahran, Xiaorong Gu, Lisa Cardone, Remuna Marti, Nour Mouannes, Maximillian Stich, Akriti G Jain, Kateryna Fedorov, Benjamin K Tomlinson, Mendel Goldfinger, Amit Verma, Yogen Saunthararajah.
      Acute myeloid leukemias (AMLs) containing TP53 (p53) mutations are routinely treated with decitabine or 5-azacytidine which deplete DNA methyltransferase 1 (DNMT1)('hypomethylating agents', HMA). Unfortunately, resistance/relapse, characterized by preserved DNMT1, is rapid. HMA are pyrimidine analogs, and to deplete DNMT1, must compete with endogenous pyrimidines. These were substantially increased in HMA-resistant versus parental AML cells, together with upregulation of carbamoyl-phosphate-synthetase-2/aspartate transcarbamylase/dihydroorotase (CAD) that rate-limits de novo pyrimidine synthesis. Moreover, TP53-mutated AMLs appeared primed for such resistance with baseline higher CAD. Pyrimidine synthesis can be depowered by using the BCL2-inhibitor venetoclax to release BAX to depolarize mitochondrial membranes. However, BAX, a p53-target gene, was ~2-fold less expressed in TP53-mutated vs TP53-wildtype cells, and venetoclax impacts were correspondingly limited. Alternatively, pyrimidine synthesis can be inhibited directly at dihydroorotate dehydrogenase (DHODH) using the clinical drug teriflunomide. Contrasting with venetoclax, teriflunomide decreased pyrimidines several-fold, restored DNMT1-depletion, and cytoreduced HMA-resistant TP53-mutated AML cells via p53/apoptosis-independent terminal lineage-maturation. This non-cytotoxic pathway preserved viability and proliferation of normal hematopoietic stem/progenitor cells (HSPC). Inhibiting pyrimidine synthesis triggered automatic increases in pyrimidine salvage, such that schedules for teriflunomide combination with HMA, taken-up by salvage, mattered: in mice with TP53-mutated AML, teriflunomide scheduled day-before HMA was more efficacious than same-day or day-after. Chronic teriflunomide exposure paradoxically increased pyrimidines via sustained compensatory pyrimidine salvage, conferring resistance rather than sensitivity to HMA. In sum, DNMT1- and DHODH-targeting, administered by timed-intermittent (metronomic) schedules, can circumvent genetic-resistance caused by TP53-mutations, and adaptive-resistance caused by metabolic homeostasis, without cytotoxicity to normal HSPC.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016683
  3. Expert Rev Mol Diagn. 2025 Oct 10.
    Mutation profiling of chronic myeloproliferative neoplasms: improving clinical-molecular prognostic models.
    Giuseppe G Loscocco, Naseema Gangat, Paola Guglielmelli, Alessandro M Vannucchi, Ayalew Tefferi.
       INTRODUCTION: Classic myeloproliferative neoplasms (MPN), comprising polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), both primary and secondary to PV and ET, are clonal hematopoietic disorders characterized by abnormal proliferation of largely mature cells, commonly associated with JAK2, CALR, or MPL mutations. These mutations result in the constitutive activation of the JAK-STAT pathway. Furthermore, most patients - especially with MF- have additional mutations in genes associated with myeloid neoplasms, which encode proteins that play roles in chromatin modification, DNA methylation, mRNA splicing, transcriptional regulation, and oncogenesis.
    AREA COVERED: This review details the molecular landscape of MPN and examines its impact on patient management. It also evaluates emerging artificial intelligence-based prognostic models, highlighting their advantages and limitations.
    EXPERT OPINION: High throughput genomic characterization of MPN has identified clinically relevant driver and non-driver mutations. Driver mutations are crucial for diagnosis, monitoring post-transplantation, and treatment response in clinical trials and increasingly in routine practice. Mutation profiles, along with cytogenetic, histopathologic, and clinical data, are used to categorize patients by risk for thrombosis, survival, and progression to secondary leukemia. The identification of a molecular enhanced scoring system for secondary myelofibrosis and clinically relevant co-mutation patterns capable to predict specific outcomes are under investigation.
    Keywords:  essential thrombocythemia; myelofibrosis; myeloproliferative neoplasms; polycythemia vera; prognosis; survival
    DOI:  https://doi.org/10.1080/14737159.2025.2573466
  4. Br J Haematol. 2025 Oct;207(4): 1648-1652
    CD123 expression and its correlation with mutation profile in acute myeloid leukaemia.
    Roberta S Azevedo, Sa A Wang, David M Swanson, Naval G Daver, Naveen Pemmaraju, Tapan M Kadia, Ghayas C Issa, Musa Yilmaz, Gautam Borthakur, Jayastu Senapati, Wei-Ying Jen, Nicholas J Short, Farhad Ravandi, Wei Wang, Hong Fang, Jie Xu, Keyur P Patel, Guilin Tang, L Jeffrey Medeiros, Courtney D DiNardo, Sanam Loghavi.
      
    Keywords:  AML subtypes; CD123 MFI; CD123 expression; genetic mutations
    DOI:  https://doi.org/10.1111/bjh.70043
  5. Leukemia. 2025 Oct 07.
    Genetic and epigenetic alterations at secondary resistance after continued decitabine-based treatment of acute myeloid leukemia in the randomized phase II DECIDER trial.
    Inga Hund, Maria Elena Hess, Geoffroy Andrieux, Julia Stomper, Gabriele Greve, Christoph Niemöller, Tobias Ma, David Uhl, Olga Grishina, Felicitas Thol, Michael Heuser, Gesine Bug, Martina Crysandt, Andreas Neubauer, Justus Duyster, Hartmut Döhner, Melanie Boerries, Michael Lübbert, Heiko Becker.
      
    DOI:  https://doi.org/10.1038/s41375-025-02780-7
  6. Blood Adv. 2025 Oct 06. pii: bloodadvances.2025016444. [Epub ahead of print]
    FLT3-ITD measurable residual disease from the QuANTUM-First trial.
    Mark J Levis, Harry P Erba, Pau Montesinos, Hee-Je Kim, Radovan Vrhovac, Elzbieta Patkowska, Pavel Zak, Po-Nan Wang, Jaime E Connolly Rohrbach, Ken Chang, Li Liu, Yasser Mostafa Kamel, Karima Imadalou, Arnaud Lesegretain, Jorge E Cortes, Mikkael A Sekeres, Hervé Dombret, Sergio Amadori, Jianxiang Wang, Richard F Schlenk, Alexander E Perl.
      QuANTUM-First was a randomized trial that demonstrated that the addition of quizartinib, a potent and selective FLT3 inhibitor, to induction and consolidation chemotherapy, followed by monotherapy maintenance, improved the survival for patients with newly diagnosed FLT3-ITD (FMS-like tyrosine kinase 3‒internal tandem duplication)--mutated acute myeloid leukemia (AML). We conducted a post-hoc analysis of the trial data focusing on measurable residual disease (MRD) as assayed using an amplicon-based next-generation sequencing assay and on the impact of molecular biomarkers such as FLT3-ITD insertion length and co-mutations. This is the first prospective, randomized trial of a FLT3 inhibitor in newly diagnosed patients in which FLT3-ITD MRD data were collected throughout therapy. We established that quizartinib induces deeper remissions with respect to FLT3-ITD MRD vs placebo, and that the amount of MRD at the completion of induction correlates with relapse and survival. We found that longer FLT3-ITD insertion mutations correlated with worse outcome, quizartinib was beneficial irrespective of insertion mutation length, and the FLT3-ITD MRD assay was more sensitive when bone marrow was used vs peripheral blood. Regardless of the presence of NPM1 co-mutation, quizartinib increased the rates of MRD-negative patients at the end of induction vs placebo. Finally, comparison of the FLT3-ITD mutation length between the polymerase chain reaction (PCR) with capillary electrophoresis assay obtained at screening and the PCR next-generation sequencing MRD assay performed at the end of induction showed a 96.2% concordance with the exact ITD length. This trial was registered at www.ClinicalTrials.gov as NCT02668653.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016444
  7. Leuk Res. 2025 Oct 06. pii: S0145-2126(25)00608-3. [Epub ahead of print]158 108118
    Applicability of current prognostication models for MDS patients with DDX41 mutation.
    Nadia Toumeh, Yazan Jabban, Rong He, David Viswanatha, Dragan Jevremovic, Patricia T Greipp, James M Foran, Talha Badar, Cecilia Y Arana Yi, Yael Kusne, Antoine N Saliba, Mehrdad Hefazi Thorghabeh, Aasiya Matin, William J Hogan, Mithun V Shah, Abhishek A Mangaonkar, Mrinal M Patnaik, Hassan B Alkhateeb, Aref Al-Kali.
      
    Keywords:  DDX41; MDS; Prognosis
    DOI:  https://doi.org/10.1016/j.leukres.2025.108118
  8. Blood Adv. 2025 Oct 06. pii: bloodadvances.2025017194. [Epub ahead of print]
    Matched Unrelated vs Haploidentical Donor Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.
    Dipenkumar Modi, Yosra M Aljawai, Todd E DeFor, Caitrin Bupp, Monzr M Al Malki, Javier Bolaños-Meade, Mahasweta Gooptu, Antonio M Jimenez Jimenez, Hongtao Liu, Felix Mensah, Marco Mielcarek, Brian C Shaffer, Bronwen E Shaw, Stephen R Spellman, Heather E Stefanski, Jeffery J Auletta, Steven M Devine, Farhad Khimani, Ramzi Abboud.
      Post-transplant cyclophosphamide (PTCy)-based graft-vs-host disease (GVHD) prophylaxis is the new standard for matched unrelated donor (MUD) hematopoietic cell transplantation (HCT). Prior studies comparing MUD and haploidentical donor HCT using PTCy were limited by size and short follow-up. We therefore performed a registry-based analysis examining the impact of donor type on HCT with PTCy. Adult patients (n=5,873) who received MUD (n=1,973) or haploidentical (n=3900) HCT with PTCy for acute leukemia (74.2%) or myelodysplastic syndrome (25.8%) reported to the CIBMTR between 2017- 2021 were included. Primary endpoints were three-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS). Cox regression and sensitivity analyses were performed through adjustment of propensity scores. Haploidentical HCT had worse OS (Hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.04-1.27, p=0.005) and GRFS (HR 1.19, 95% CI 1.10-1.29, p<0.001) compared to MUD HCT. Donor age was the only other consistent donor-related factor associated with survival. Results were confirmed in a sensitivity analysis adjusted for propensity scores. When the cohort was restricted to reduced intensity conditioning only or donors <30 years-old, OS did not differ between groups. Haploidentical HCT was associated with higher primary graft failure (HR 1.67; p=0.002), increased grade III-IV acute GVHD (HR 1.28; p=0.039), higher moderate/severe chronic GVHD (HR 1.47; p<0.001) and non-relapse mortality (HR 1.34; p<0.001). Grade II-IV aGVHD and relapse risk did not differ between the donor types. This large analysis showed that in adults with acute leukemia or MDS, MUD HCT was associated with improved outcomes compared to haplo HCT with PTCy-based GVHD prophylaxis.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017194
  9. Leuk Lymphoma. 2025 Oct 11. 1-10
    Comparison of the clinicopathological features in myeloproliferative or myelodysplastic neoplasms with SF3B1/JAK2, SF3B1/CALR, or SF3B1/MPL co-mutations.
    Richard Shao, Le Wang, Hailing Zhang, Michael Martin, Lynn Moscinski, Amy Li, Julie Li, Jinming Song.
      Mutations in JAK2, CALR, and MPL account for over 90% of Philadelphia-negative (Ph-) myeloproliferative neoplasm (MPN), while SF3B1 mutations are diagnostic for myelodysplasia in myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Concurrent mutations of SF3B1 with JAK2, CALR, or MPL in myeloid neoplasms have not been extensively studied. We identified a total of 136 cases with SF3B1/JAK2 (SJ), SF3B1/CALR (SC), and SF3B1/MPL (SM) co-mutations and demonstrated that SJ, SC, and SM co-mutations are prevalent across various myeloid neoplasms, with the highest frequency observed in MPN and MDS/MPN, and with SJ representing the most common co-mutation. MDS/MPN with SF3B1 mutation and thrombocytosis shows the strongest overall association with SJ, SC, and SM co-mutations. Primary myelofibrosis shows the strongest association with the three co-mutations within MPN. JAK2 VAF levels differ significantly among MPN, MDS/MPN, and MDS. MDS cases with these co-mutations had significantly poorer overall survival compared to MPN and MDS/MPN cases.
    Keywords:  AML; CALR; JAK2; MDS; MDS/MPN; MPL; MPN; Myeloproliferative neoplasms; SF3B1; acute myeloid leukemia; co-mutations; myelodysplastic neoplasms; myelodysplastic/myeloproliferative neoplasms
    DOI:  https://doi.org/10.1080/10428194.2025.2554339
  10. Leuk Lymphoma. 2025 Oct 10. 1-11
    Clinical outcomes of allogeneic cell transplantation for patients with chronic myeloid leukemia.
    Benjamin McCormick, Anthony Findley, Kendall Diebold, Garrett Bourne, Maris Hardee, James Foran, Mohamed Kharfan-Dabaja, Hemant Murthy, Madiha Iqbal, Naseema Gangat, Lisa Sproat, Jeanne Palmer, William J Hogan, Kebede Begna, Mark Litzow, Ayalew Tefferi, Mrinal Patnaik, Ravi Bhatia, Omer Jamy, Talha Badar.
      Allogeneic hematopoietic cell transplantation (allo-HCT) remains a key treatment for patients with chronic myeloid leukemia (CML) in blast phase (CML-BP) or tyrosine kinase inhibitor (TKI)-resistant chronic phase (CML-CP). We retrospectively analyzed 75 patients who underwent allo-HCT at four U.S. centers from 2005 to 2023. Of these, 60 had CML-BP (26 myeloid, 34 lymphoid) and 15 had TKI-resistant CML-CP. Median overall survival (OS) was 50 months in myeloid blast phase (MBP) and not reached in lymphoid blast phase (LBP) or CML-CP. MBP had higher relapse rates and inferior leukemia-free survival (LFS) compared to LBP and CML-CP. Outcomes were worse in transformed MBP versus de novo MBP, and in those with 7/7q- deletions. Post-HCT TKI maintenance did not significantly affect relapse or survival. Our findings support allo-HCT as an effective treatment option in CML-BP and TKI-resistant CML-CP, with outcomes influenced by disease biology and cytogenetic features at transformation.
    Keywords:  Chronic myeloid leukemia; allogeneic hematopoietic cell transplantation; tyrosine kinase inhibitor resistance
    DOI:  https://doi.org/10.1080/10428194.2025.2564766
  11. Leukemia. 2025 Oct 09.
    Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations.
    Maki Sakuma, Amy K Wang, Samuel J Magaziner, Sachiko P Keane, Manja Meggendorfer, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach, David B Beck, Wencke Walter.
      VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe inflammatory and hematologic disease caused by somatic mutations in UBA1. Canonical pathogenic mutations at UBA1 p.Met41 (M41) lead to the loss of the cytoplasmic isoform (UBA1b), while non-canonical mutations outside of M41 (non-M41) result in reduced activity of both nuclear and cytoplasmic isoforms. Studies have reported clinical differences between canonical and non-canonical mutations, but these findings are constrained by small sample sizes and scarcity of genetic studies. In our study, we screened 29,000 individuals for UBA1 variants, referred for a broad range of hematologic diseases, and subjected to 62-gene panel sequencing, identifying 232 patients carrying likely disease-causing mutations. We identified decreased polyubiquitylation in all of the 18 UBA1 variants tested and found differences in H2A/B monoubiquitylation alteration between M41 and non-M41 mutations. Our findings confirm that patients harboring M41 mutations present at most with myelodysplastic neoplasms (MDS) and suggest that M41 mutations generally do not tolerate multiple co-mutations. In contrast, non-M41 mutations are more likely to appear with co-mutations and are detected in patients with hematologic neoplasms other than MDS. Our study establishes that M41 and non-M41 mutations exhibit distinct clinical and biological phenotypes, significantly enhancing UBA1 variant interpretation.
    DOI:  https://doi.org/10.1038/s41375-025-02775-4
  12. Blood. 2025 Oct 07. pii: blood.2024026505. [Epub ahead of print]
    A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.
    Francesca Matteini, Roshana Thambyrajah, Sara Montserrat-Vazquez, Sascha Jung, Alba Ferrer-Perez, Patricia Herrero Molinero, Dina El Jaramany, Javier Lozano-Bartolomé, Eva Mejia-Ramirez, Jessica Gonzalez Miranda, Antonio Del Sol, Anna Bigas, Maria Carolina Florian.
      Aged hematopoietic stem cells (HSCs) expand in clusters over time, while reducing their regenerative capacity and their ability to preserve the homeostasis of the hematopoietic system. The expression of Notch ligands in the bone marrow (BM) niche is essential for hematopoiesis. However, the impact of Notch signaling for adult HSC function and its involvement in HSC aging remains controversial. Here we show that Notch activation in young HSCs is not homogeneous, and it is triggered by sinusoidal expression of the Notch ligand Jagged2 (Jag2). Sinusoidal Jag2 deletion in young mice recapitulates the decrease in Notch activity observed in aged HSCs and alters HSC divisional symmetry and fate priming, promoting myeloid-biased HSCs (My-HSCs) expansion. Mechanistically, our data reveals that upon decreasing sinusoidal Jag2 expression, HSCs themselves upregulate Jag2, which cis-inhibits Notch signaling, resulting in the expansion of My-HSCs and in reduced hematopoietic regeneration. Collectively, these findings identify the crosstalk between BM niche-driven and HSC intrinsic features in regulating HSC fate priming and regenerative potential and reveal an extrinsic Notch trans-activation to intrinsic cis-inhibition switch underlying HSC aging.
    DOI:  https://doi.org/10.1182/blood.2024026505
  13. Blood Adv. 2025 Oct 08. pii: bloodadvances.2025017035. [Epub ahead of print]
    Transplantation in lower risk MDS patients: a prospective phase 2 trial based on donor availability.
    Marie Sebert, Sylvain Thepot, Thomas Cluzeau, Nicolas Duployez, Thibaud Lefebvre, Cendrine Chaffaut, Corentin Orvain, Michael Loschi, Pierre Peterlin, Patrice Chevallier, Maud D'Aveni, Marie-Thérèse Rubio, Odile Rauzy, Anne Huynh, Amandine Charbonnier, Rosa Sapena, Fatiha Chermat, Patrice Ceballos, Gaelle Fossard, Stephanie Nguyen, Sophie Park, Lionel Adès, Régis Peffault De Latour, Claude Preudhomme, Pierre Fenaux, Sylvie Chevret, Marie Robin.
      Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potential curative therapy for myelodysplastic syndrome (MDS), recommended in higher-risk according to IPSS. We conducted a phase II multicenter trial (MDS-ALLO-RISK, CNT: NCT02757989) investigating whether allogeneic hematopoietic stem cell transplantation (HSCT) improves overall survival (OS) in patients with lower-risk myelodysplastic syndromes (MDS) who exhibit additional high-risk features (intermediate or higher IPSS-R risk, thrombocytopenia < 20 G/L, neutropenia < 0.5 G/L or failure to 2 lines of therapy). A total of 77 patients (median age 62.5) with low or intermediate-1 IPSS scores were enrolled and stratified based on the presence of a matched HLA donor: 62 patients in the donor arm and 15 without a donor . Despite high remission rates in transplanted patients (67.8% vs. 21.4%), the 3-year OS did not significantly differ between arms (57.6% in donor arm vs. 64.3% in non-donor arm, HR 0.75, p=0.53). The adjusted analysis using inverse probability of treatment weighting (IPTW) confirmed the lack of survival benefit with HSCT. Transplantation was associated with higher rates of chronic graft-versus-host disease (GVHD), severe infections, and non-relapse mortality (24.7%). Although quality of life improved slightly over time in transplanted patients, the difference was not statistically significant. The trial was stopped early due to slow enrollment and futility. The findings highlight the need for improving post-transplant outcomes to justify HSCT in lower-risk MDS patients with poor prognostic features.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017035
  14. Nat Commun. 2025 Oct 08. 16(1): 8964
    The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia.
    Louise Ahlgren, Mattias Pilheden, Helena Sturesson, Guangchun Song, Michael P Walsh, Minjun Yang, Maud Maillard, Huanbin Zhao, Zhongshan Cheng, Varsha Singh, Anders Castor, Cornelis Jan Pronk, Hanne Vibeke Marquart, Birgitte Lausen, Pauline Schneider, Gisela Barbany, Katja Pokrovskaja Tamm, Jonas Abrahamsson, Olli Lohi, Linda Fogelstrand, Pablo Menendez, Rob Pieters, Jinghui Zhang, Karin Lindkvist-Petersson, Jun J Yang, Tanja A Gruber, Ronald W Stam, Jing Ma, Anna K Hagström-Andersson.
      To study the mechanisms of relapse in KMT2A-rearranged (KMT2A-r) acute lymphoblastic (ALL) and acute myeloid leukemia (AML), we performed whole-genome and exome sequencing of infants and children with relapsed ALL/AML (n = 36), and longitudinal deep-sequencing of 257 samples in 30 patients. Somatic alterations in drug-response genes, most commonly in TP53 and IKZF1 (64%), were highly enriched in early relapse ALL (79%, 9-36 months after diagnosis), but rare in very early relapse ALL (<9 months, 9%). A marked chemotherapy-exposure signature was detected for mutations in early relapse ALL but not in very early ALL or AML relapse, in line with different mechanisms of relapse. Longitudinal analyses could track residual leukemia cells, clonal drug responses, and the upcoming relapse. These results highlight that KMT2A-r ALL and AML evade therapy differently and provide insights into the mechanisms of relapse in this highly lethal form of pediatric acute leukemia.
    DOI:  https://doi.org/10.1038/s41467-025-64190-8
  15. Blood Cancer J. 2025 Oct 06. 15(1): 157
    Allogeneic stem cell transplantation in chronic myelomonocytic leukemia: analysis of post-transplant survival and risk factors in 138 Mayo Clinic patients.
    Ali Alsugair, Estefania Gauto Mariotti, Mohammad M Alhousani, Saubia Fathima, Muhammad Yousuf, Abiola Bolarinwa, James Foran, Abishek A Mangaonkar, Mark Litzow, Hemant Murthy, Lisa Sproat, Jeanne Palmer, Aasiya Matin, Ernesto Ayala, James Slack, Luis Porrata, Madiha Iqbal, Nandita Khera, Nathan Punwani, Saad Kenderian, Saurabh Chhabra, William J Hogan, Mithun Vinod Shah, Hassan B Alkhateeb, Naseema Gangat, Mrinal Patnaik, Ayalew Tefferi.
      Allogeneic stem cell transplant (ASCT) remains the only curative option in chronic myelomonocytic leukemia (CMML). We retrospectively analyzed 138 CMML patients who underwent ASCT at the Mayo Clinic. Patients who transitioned to ASCT while in chronic phase (Group A) displayed superior post-transplant survival (PTS), compared to those in whom ASCT was performed after blast transformation (BT; Group B) (median 95 vs. 16 months; p = 0.01). In Group A, PTS was superior in patients with <5% bone marrow (BM) blasts at time of ASCT (median 164 vs. 13.5 months; p = 0.01). Other predictors of superior PTS included day-100 BM blast <5% or normal cytogenetics (median 164 vs. 18 months; p = 0.01) or presence of chronic graft-versus-host-disease (GVHD; median 164 vs. 26 months; p = 0.01). Pre-ASCT hypomethylating agent exposure (HR = 2.03; p = 0.03), and receiving more than one line of pre-ASCT chemotherapy (p = 0.01) predicted inferior PTS. In multivariable analysis, predictors of superior GVHD-free and relapse-free survival (GRFS) included the use of myeloablative conditioning and the absence of morphologically or cytogenetically apparent disease at day-100. The use of post-transplant cyclophosphamide (PTCy) was associated with a higher cumulative incidence of relapse (p = 0.02) and numerically inferior PTS (p = 0.1). Group B patients also appeared to benefit from achieving BM blast <5% at the time of ASCT (p = 0.4) as well as at day-100 (p = 0.01), in terms of PTS, while full chimerism and normal cytogenetics at day-100 were associated with superior GRFS. These observations support the value of ASCT in CMML, especially if performed prior to BT and in the presence of <5% BM blasts at the time of ASCT. Additionally, the observed detrimental impact of PTCy requires additional studies to confirm and investigate the underlying mechanisms.
    DOI:  https://doi.org/10.1038/s41408-025-01359-w
  16. Br J Haematol. 2025 Oct;207(4): 1694-1697
    Pretransplant MRD and chemotherapy in AML: A transplant physician's perspective.
    Alaa Ali.
      
    Keywords:  acute myeloid leukaemia; allogeneic stem cell transplant; bridging chemotherapy; graft‐versus‐leukaemia (GVL); measurable residual disease (MRD); post‐remission therapy
    DOI:  https://doi.org/10.1111/bjh.70048
  17. Blood. 2025 Oct 08. pii: blood.2025029513. [Epub ahead of print]
    Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche.
    James W Swann, Ruiyuan Zhang, Evgenia V Verovskaya, Fernando J Calero-Nieto, Xiaonan Wang, Melissa A Proven, Hiroyuki Hirakawa, Brian P Heubel, Peter T Shyu, X Edward Guo, Lei Ding, Berthold Gottgens, Emmanuelle Passegue.
      Hematopoietic stem and progenitor cells (HSPC) are regulated by interactions with stromal cells in the bone marrow (BM) cavity, which can be segregated into two spatially defined central marrow (CM) and endosteal (Endo) compartments. However, the importance of this spatial compartmentalization for BM responses to complex conditions like inflammation remains largely unknown. Here, we extensively validate a combination of scRNA-seq profiling and matching flow cytometry isolation that reproducibly identifies 7 key CM and Endo populations and accurately surveys both niche locations. We demonstrate that inflammatory perturbations exert specific effects on different cellular compartments, with type I interferon responses causing leptin receptor-expressing mesenchymal stromal cells to abandon their normal stromal functions and instead adopt an inflammatory phenotype associated with overproduction of chemokines that modulate local monocyte dynamics in the surrounding microenvironment. Our results provide a comprehensive method for molecular and functional stromal characterization and highlight the importance of altered stomal cell activity in regulating hematopoietic responses to inflammatory challenges.
    DOI:  https://doi.org/10.1182/blood.2025029513
  18. Blood Cancer J. 2025 Oct 06. 15(1): 158
    Assessing drivers of disparate outcomes and applicability of risk stratification in a cohort of patients with myelofibrosis.
    Andrew Palmer, Garth Rauscher, Alexa Schoen, Madelyn Burkart, Ashley Dunton, Cherry Au, Ami Dave, Ahmad Nassar, Shaoshi Zhu, Alexander O'Hara, Nusrat Africawala, Amani Erra, Vinod Solipuram, Ivy Abraham, Stephanie B Tsai, Maryam Zia, Melissa L Larson, Damiano Rondelli, Jessica K Altman, Wendy Stock, Irum Khan, Olatoyosi Odenike, Anand Ashwin Patel.
      
    DOI:  https://doi.org/10.1038/s41408-025-01366-x
  19. Leuk Lymphoma. 2025 Oct 10. 1-10
    Clinical and biological predictors of treatment-free remission in CML.
    Edwina Sutton, Naranie Shanmuganathan, David Ross.
      Chronic Myeloid Leukemia (CML) is characterized by the Philadelphia chromosome t(9:22) and results in the BCR::ABL1 fusion gene. Since the evolution of targeted therapy in the form of tyrosine kinase inhibitors (TKIs), overall survival has improved to 94% at 5 years. Early studies identified that approximately half of patients could maintain a major molecular remission (MMR), i.e. BCR::ABL1 ≤ 0.1%, in the absence of TKI therapy. This is termed treatment-free remission (TFR). Identifying clinical and biological predictors of TFR has become a major goal in CML. In this review, we discuss clinical predictors of TFR, including features at diagnosis, molecular response and kinetics, depth and duration of molecular response, and dose reduction prior to TKI cessation in determining TFR success. We also discuss advances in highly sensitive Minimal Residual Disease (MRD) assays, consider the genomic profile of CML patients and review the role of the immune environment in sustaining TFR.
    Keywords:  BCR::ABL1; CML; TFR; TKI; biomarkers; drug discontinuation
    DOI:  https://doi.org/10.1080/10428194.2025.2560081
  20. Blood Adv. 2025 10 07. pii: bloodadvances.2025016507. [Epub ahead of print]
    Germline LCP1 mutations cause immunodeficiency with neutropenia, monocytopenia, lymphopenia and defective cytokinesis.
    Thijs van Bergen, Dennis Bosch, Christine Bellanné-Chantelot, Roger Mulet-Lazaro, Jacob R Bledsoe, Lanpeng Chen, Hans W J de Looper, Claire van Dijk, Mariëtte Ter Borg, Eric Bindels, Remco Hoogenboezem, Onno Roovers, Patricia A Olofsen, Marije Bartels, Joris M van Montfrans, Puck Breed, Elisabeth Salzer, Marloes G Holierhoek, Brigittie Nelken, Blandine Beaupain, Mark Daniel Fleming, Akiko Shimamura, Marc H G P Raaijmakers, Jean Donadieu, Peter E Newburger, Ivo P Touw, Anna M Aalbers.
      Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent infections and an increased leukemia risk. Multiple genetic defects underlying SCN have been identified, but a genetic diagnosis is still lacking in a significant proportion of patients. Here, we report four independent pedigrees with heterozygous variants in LCP1. Variants c.740-1G>T and c.740-20_744del resulted in the same alternatively spliced RNA product, causing an in-frame deletion (p.A247_E254del). Variant c.509C>T in the third pedigree resulted in p.S170L, and variant c.806T>C in the fourth pedigree in p.L269P. Affected individuals suffer from neutropenia, poor or complete lack of response to G-CSF treatment, and variable degrees of lymphopenia, hypogammaglobulinemia, and monocytopenia. Patients with A247_E254del and p.L269P presented with tetraploid cells in the bone marrow, indicative of disturbed cytokinesis. In one of these kindreds, two individuals developed acute leukemia. G-CSF non-responsiveness and defective cell cycling were repaired upon correction of the LCP1 A247_E254del variant in patient-derived induced pluripotent stem cells, supporting the monogenic origin of the disease. Indicative of their gain-of-function, both A247_E254del and S170L variants increased F-actin bundling and formation of abnormal protrusions. Single-cell transcriptome analysis of A247_E254del bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) showed deregulation of signaling pathways controlling mitosis in multi-lineage and lymphoid-primed HSPC subsets. We conclude that activating LCP1 variants cause a new hematopoietic disorder with autosomal dominant inheritance. Depending on the consequences of the LCP1 variants for protein structure, patients may suffer from G-CSF refractory severe neutropenia, lymphopenia, hypogammaglobulinemia, monocytopenia, and defective cytokinesis.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016507
  21. Semin Hematol. 2025 Aug 29. pii: S0037-1963(25)00036-8. [Epub ahead of print]
    The immunotherapy landscape in AML: Defining knowledge gaps toward rational combinatorial strategies.
    Marion Subklewe, Sergio Rutella, Antonio Curti.
      Immunotherapy has dramatically improved outcomes in lymphoid malignancies. In B cell cancers, CD19-directed CAR T cells and T-cell engagers have produced high remission rates and durable responses, now forming the cornerstone of treatment in many relapsed or refractory settings. In contrast, acute myeloid leukemia (AML) has not experienced a comparable breakthrough. To date, only antibody-drug conjugates have reached regulatory approval, with gemtuzumab ozogamicin approved in combination with intensive induction and consolidation therapy for newly diagnosed CD33-positive AML. This divergence is rooted in the biological and immunologic complexity of AML. Unlike B-cell malignancies with lineage-restricted surface markers such as CD19, AML lacks leukemia-specific antigens. Most targets are shared with normal hematopoietic progenitors, leading to on-target/off-leukemia toxicity. Moreover, AML exerts local and systemic immunosuppression through both tumor-intrinsic and microenvironmental mechanisms, limiting T-cell persistence and function. This review will introduce the current immunotherapy platforms under investigation in AML, starting with antibody-based approaches, followed by T-cell redirecting therapies, and culminating in an overview of immune resistance, the bone marrow microenvironment, and strategies toward personalized combinatorial immunotherapy. By synthesizing recent clinical data and mechanistic insights, including those from early CAR and T-cell engager trials, we aim to provide a translational framework for how immunotherapy might still reshape AML care-through integration of immune contexture of the bone marrow environment aiming for rational combinatorial approaches.
    Keywords:  ADCs; AML; CART; Immunotherapy; T cell engagers
    DOI:  https://doi.org/10.1053/j.seminhematol.2025.08.003
  22. Leukemia. 2025 Oct 10.
    Heart failure in patients with acute myeloid leukemia (AML) treated with anthracycline agents during remission induction therapy: a systematic review and meta-analysis.
    Jesse Geels, Anna van Rhenen, Patrycja Gradowska, Folkert W Asselbergs, Marijke Linschoten.
      Patients with acute myeloid leukemia (AML) are at increased risk of cardiovascular disease, particularly heart failure. Anthracyclines are integral to remission induction therapy in patients eligible for intensive treatment and well-known for their association with cardiotoxicity. However, the incidence of heart failure and other cardiovascular adverse events (CVAEs), as well as differences across various anthracycline agents, has not been comprehensively assessed. We systematically searched PubMed and EMBASE for studies conducted in AML patients treated with anthracyclines during remission induction. Forty-one studies (5995 patients), primarily clinical trials, published between February 1991 and March 2024 were included. The pooled proportion of heart failure was 3.2% (95% CI 1.0-6.2) overall and 2.3% (95% CI 1.4-3.3), 5.0% (95% CI 0.3-14.1) and 10.2% (95% CI 2.4-21.7) for patients treated with daunorubicin, idarubicin or mitoxantrone respectively. Cardiac function was infrequently monitored, and CVAE reporting was generally poor. Since current adverse event grading systems primarily rely on clinical symptoms to assign severity, significant asymptomatic declines in cardiac function will remain undetected. Enhanced CVAE monitoring and reporting, along with revisions to established grading systems, is needed to better identify subclinical cardiotoxicity in AML patients, enabling timely intervention to prevent progression to more advanced heart failure stages.
    DOI:  https://doi.org/10.1038/s41375-025-02753-w
  23. Blood Adv. 2025 Oct 07. pii: bloodadvances.2025017601. [Epub ahead of print]
    Phase I Study of Rogocekib in Patients with Relapsed or Refractory Hematologic Malignancies.
    Hisayuki Yokoyama, Noriko Fukuhara, Koji Ando, Hiroatsu Iida, Takahiro Yamauchi, Suguru Fukuhara, Koji Izutsu, Yasushi Tanoue, Maki Yamamoto, Hirokazu Tozaki, Eiji Takahara, Shingo Shoji, Akio Mizutani, Daisuke Morishita, Robert Westley Oda, Hiroshi Miyake, Noboru Yamamoto.
      Rogocekib (development name CTX-712) is a first-in-class, orally available, highly potent, and selective small molecule inhibitor of CDC2-like kinase (CLK), a key regulator of the RNA splicing process. Preclinical studies demonstrated anti-proliferative activity on various in-vitro and in-vivo models of hematologic malignancies. Based on these findings, a phase I study of rogocekib was conducted to evaluate the safety and preliminary efficacy in patients with relapsed or refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS). Using a 3+3 design informed by prior solid tumor safety data, patients received 70 mg or 105 mg twice a week (TW) in capsule form. One dose limiting toxicity (DLT) of Grade 4 Pneumonia was observed in the 105 mg TW cohort. Among 12 AML patients, complete remission (CR) was observed in 3 patients (25.0%), and CR with incomplete hematologic recovery (CRi) was observed in 1 patient (8.3%). In MDS patients (n=2), CR was observed in 1 patient (50.0%). Pharmacokinetics (PK) analyses showed higher mean Cmax and AUC0-24 of rogocekib at 105 mg compared to 70 mg. Pharmacodynamics (PD) analysis showed that the relative magnitude of exon skipping in peripheral blood cells increased with exposure of rogocekib. Rogocekib demonstrated a manageable and tolerable safety profile in patients with hematologic malignancies. This study was registered on the Japan Registry of Clinical Trials under jRCT2080224127. Currently, a Phase I/II Study of rogocekib in relapsed/refractory AML and higher risk MDS is ongoing in the United States (NCT05732103).
    DOI:  https://doi.org/10.1182/bloodadvances.2025017601
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