bims-tremyl 2025-03-02 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2025–03–02
thirty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Magrolimab plus azacitidine vs physician's choice for untreated TP53-mutated acute myeloid leukemia: the ENHANCE-2 study.
Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia.
A CEBPB/IL-1β/TNF-α Feedback Loop Drives Drug Resistance to Venetoclax and MDM2 Inhibitors in Monocytic Leukemia.
Haploinsufficiency of miR-143 and miR-145 reveal targetable dependencies in resistant del(5q) myelodysplastic neoplasm.
Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.
Molecular Predictors of Response and Survival in Patients with Relapsed/Refractory Acute Myeloid Leukemia following Venetoclax plus Hypomethylating Agent Therapy.
cMPL-Based Purification and Depletion of Human Hematopoietic Stem Cells: Implications for Pretransplant Conditioning.
Posttranscriptional activity of the eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis.
Sex differences alter primitive progenitors in the C57BL/6 Tet2 knockout mouse model.
CD34+CD38- leukemia stem cells predict clinical outcomes in acute myeloid leukemia patients treated non-intensively with hypomethylating agents.
STING mediates increased self-renewal and lineage skewing in DNMT3A-mutated hematopoietic stem/progenitor cells.
Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.
Venetoclax and Decitabine vs Intensive Chemotherapy as Induction for Young Patients with Newly Diagnosed AML.
MENIN MAINTENANCE THERAPY FOR ACUTE LEUKEMIA.
Use of Primary Prophylaxis with G-CSF in Acute Myeloid Leukemia Patients Undergoing Intensive Chemotherapy Does Not Affect Quality of Response.
Cladribine Added to Idarubicin and Cytarabine as an Induction Regimen for Patients with De Novo Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Trial.
Decoding functional hematopoietic progenitor cells in the adult human lung.
STING activation improves T-cell-engaging immunotherapy for acute myeloid leukemia.
Prognostic relevance of variant allelic frequency for treatment outcomes in patients with acute myeloid leukemia: a study by the Spanish PETHEMA registry.
Identification of new candidate drugs in myelodysplastic syndromes with splicing factor mutations by transcriptional profiling and connectivity map analysis.
Gastrointestinal toxicity of Gemtuzumab Ozogamicin: Real-life data from the AMLCG, SAL and CELL study groups.
Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.
NOTCH1 dimeric signaling is essential for T-cell leukemogenesis and leukemia maintenance.
Discovery of selective, metabolically stable pyrazole-based FLT3 inhibitors for the treatment of acute myeloid leukemia.
Single-cell analysis of aplastic anemia reveals a convergence of NK and NK-like CD8+ T cells with a disease-associated TCR signature.
Long-term patient-reported outcomes following allogeneic hematopoietic cell transplantation.
Comparison of recognition of symptom burden in MPN between patient- and physician-reported assessment - an intraindividual analysis by the German Study Group for MPN (GSG-MPN).
Maintenance therapy with oral decitabine plus cedazuridine after allogeneic stem cell transplantation for myelodysplastic syndrome.
A First-in-Class JAK/ROCK Inhibitor, Rovadicitinib, for Glucocorticoid-Refractory or -Dependent Chronic GVHD.
Systems-level design principles of metabolic rewiring in an animal.
Real-world evidence of pegcetacoplan in patients with paroxysmal nocturnal haemoglobinuria: A nationwide Italian study.

Blood. 2025 Feb 26. pii: blood.2024027408. [Epub ahead of print]

Magrolimab plus azacitidine vs physician's choice for untreated TP53-mutated acute myeloid leukemia: the ENHANCE-2 study.

Joshua F Zeidner, David A Sallman, Christian Récher, Naval G Daver, Anskar Yh Leung, Devendra K Hiwase, Marion Subklewe, Thomas Pabst, Pau Montesinos, Richard A Larson, Lindsay Wilde, Anoop K Enjeti, Ichiro Kawashima, Cristina Papayannidis, Jenny O'Nions, Lisa Johnson, Mei Dong, Julie Huang, Taravat Bagheri, Gal Hacohen-Kleiman, Calvin Lee, Paresh Vyas.

Patients with TP53-mutated acute myeloid leukemia (AML) have an extremely poor prognosis, necessitating new treatments. The global, randomized, phase 3 ENHANCE-2 trial evaluated the anti-CD47 monoclonal antibody magrolimab plus azacitidine (Magro/Aza) for previously untreated TP53-mutated AML. Patients determined inappropriate for intensive therapy were randomized to receive Magro/Aza or venetoclax plus azacitidine (Ven/Aza); those appropriate for intensive therapy were randomized to receive Magro/Aza or 7+3 induction chemotherapy. Primary endpoint was overall survival (OS) in the non-intensive arm. At interim analysis, non-intensive-arm OS hazard ratio (HR) between treatment groups was 1.191 (95% CI, 0.744-1.906), meeting the study's definition for futility and resulting in study termination. At final analysis, median OS was 4.4 vs 6.6 months (HR, 1.132; 95% CI, 0.783-1.637; P = .5070) in the non-intensive arm (n = 205) and 7.3 vs 11.1 months (HR, 1.434; 95% CI, 0.635-3.239; P = .3798) in the intensive arm (n = 52) between Magro/Aza and control groups, respectively. Incidences of grade ≥3 adverse events (AEs) were similar across Magro/Aza and control groups (non-intensive, n = 194: 96.9% and 95.9%; intensive, n = 50: 92.6% and 95.7%), including grade ≥3 anemia (non-intensive: 27.1% and 23.5%; intensive: 25.9% and 21.7%). Grade ≥3 infections were observed in 50.0% and 53.1% of patients in the non-intensive arm and 44.4% and 65.2% of intensive arm patients. ENHANCE-2 did not meet its primary endpoint of OS in TP53-mutated AML but provides important data informing future studies in this challenging population. This trial was registered at www.clinicaltrials.gov as #NCT04778397.

DOI: https://doi.org/10.1182/blood.2024027408
Leukemia. 2025 Feb 25.

Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia.

Courtney D DiNardo, Wei-Ying Jen, Koichi Takahashi, Tapan M Kadia, Sanam Loghavi, Naval G Daver, Lianchun Xiao, Patrick K Reville, Ghayas C Issa, Nicholas J Short, Koji Sasaki, Sa A Wang, Jillian K Mullin, Sherry Pierce, Corey Bradley, Gautam Borthakur, Abhishek Maiti, Yesid Alvarado, Naveen Pemmaraju, Alessandra Ferrajoli, Mahesh Swaminathan, Maro Ohanian, Hussein A Abbas, Danielle Hammond, Jan Burger, Fadi Haddad, Guillermo Montalban-Bravo, Kelly Chien, Lucia Masarova, Musa Yilmaz, Nitin Jain, Michael Andreeff, Guillermo Garcia-Manero, Steven Kornblau, Farhad Ravandi, Elias Jabbour, Marina Y Konopleva, Hagop M Kantarjian.

Intensive chemotherapy remains the standard for newly diagnosed (ND) acute myeloid leukemia (AML); however, relapse risk remains high. Additionally, most patients with relapsed/refractory (RR) AML have poor outcomes. We report the long-term experience of 138 patients, 77 ND and 61 RR, treated with FLAG-IDA in combination with venetoclax. In the ND cohort, the overall response rate (ORR) was 97%, with a composite complete remission (CRc) rate of 95% and undetectable measurable residual disease (MRD) status by flow cytometry in 90%. The 3-year OS and EFS rates were 66 and 64%, respectively. Outcomes were similar across European LeukemiaNet (ELN) 2022 risk groups. Sixty-four percent transitioned to allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR1. In the RR cohort, the ORR was 67%; CRc rate 41% and flow negative MRD rate 74%; 57% transitioned to allo-SCT. The patients with RR AML in first salvage with wild-type TP53 status had particularly favorable outcomes, with an ORR of 79%, CRc rate of 74% (76% MRD undetectable) and 3-year OS rate of 51%. Infectious and hematologic adverse events were common, with low 30- and 60-day mortality similar to other intensive chemotherapy regimens. FLAG-IDA + VEN is effective for remission induction in both ND and RR AML.ClinicalTrials.gov Identifier: NCT03214562.

DOI: https://doi.org/10.1038/s41375-025-02531-8
Blood. 2025 Feb 26. pii: blood.2024028239. [Epub ahead of print]

A CEBPB/IL-1β/TNF-α Feedback Loop Drives Drug Resistance to Venetoclax and MDM2 Inhibitors in Monocytic Leukemia.

Basil Allen, Daniel Bottomly, Thomas Köhnke, Anthony Wang, Hsin-Yun Lin, Kara Johnson, Isabel Kenna, Anastatia Streltsova, Emma Martin, Reid Chen, Lindsey Savoy, Nicola Long, Peter Ryabinin, Stephen E Kurtz, Christopher A Eide, Amy Carlos, Andy Kaempf, Tingting Liu, Cristina E Tognon, Robert Searles, Paul D Piehowski, Sara J C Gosline, Anupriya Agarwal, Bill H Chang, Michelle Barton, Brian J Druker, Shannon K McWeeney, Ravindra Majeti, Jeffrey W Tyner, Haijiao Zhang.

MDM2 inhibitors are promising therapeutics for acute myeloid leukemia (AML) with wild-type TP53. Through an integrated analysis of functional genomic data from primary patient samples, we found that an MDM2 inhibitor idasanutlin, like venetoclax, is ineffective against monocytic leukemia (FAB M4/M5). To dissect the underlying resistance mechanisms, we explored both intrinsic and extrinsic factors. We found that monocytic leukemia cells express elevated levels of CEBPB, which promotes monocytic differentiation, suppresses CASP3 and CASP6, and upregulates MCL1, BCL2A1, and the IL-1/TNF-α/NF-κB pathway members, conferring drug resistance to a broad range of MDM2 inhibitors, BH3 mimetics, and venetoclax combinations. Additionally, aberrant monocytes in M4/M5 leukemia produce elevated levels of IL-1 and TNF-α, which promotes monocytic differentiation and upregulate inflammatory cytokines and receptors, thereby extrinsically protecting leukemia blasts from venetoclax and MDM2 inhibition. Interestingly, IL-1β and TNF-α only increase CEBPB levels and protect M4/M5 cells from these drugs, but not M0/M1 leukemia cells. Treatment with venetoclax and idasanutlin induces compensatory upregulation of CEBPB and the IL-1/TNF-α/NF-κB pathway, independent of FAB subtype, indicating a drug induced compensatory protection mechanisms. A combination of venetoclax/ idasanutlin with inhibitors that block IL-1/TNF-α pathway, demonstrate synergistic cytotoxicity in M4/M5 AML. As such, we uncovered a targetable positive feedback loop involving CEBPB, IL-1/TNF-α, and monocyte differentiation in M4/M5 leukemia, which promotes both intrinsic and extrinsic drug resistance, along with drug-induced protection against venetoclax and MDM2 inhibitors.

DOI: https://doi.org/10.1182/blood.2024028239
Leukemia. 2025 Feb 25.

Haploinsufficiency of miR-143 and miR-145 reveal targetable dependencies in resistant del(5q) myelodysplastic neoplasm.

Nadia Gharaee, Joanna Wegrzyn-Woltosz, Jihong Jiang, Vijay Suresh Akhade, Joshua Bridgers, Ryan J Stubbins, Devendra Hiwase, Monika M Kutyna, Onyee Chan, Rami Komrokji, Eric Padron, Yu Deng, Gary Cole, Patricia Umlandt, Megan Fuller, Ada Kim, Aly Karsan.

Myelodysplastic neoplasms (MDS) are stem cell disorders characterized by ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). Chromosomal alterations are frequent in MDS, with interstitial deletion of chromosome 5q (del(5q)) being the most common. Lenalidomide is the current first-line treatment for del(5q) MDS and its efficacy relies on degradation of CK1α which is encoded by the CSNK1A1 gene located in the commonly deleted region (CDR) of chromosome 5q. However, lenalidomide-resistance is common, often secondary to loss-of-function mutations in TP53 or RUNX1. The CDR in del(5q) harbors several genes, including noncoding miRNAs, the loss of which contribute to disease phenotypes. miR-143 and miR-145 are located within the del(5q) CDR, but precise understanding of their role in human hematopoiesis and in the pathogenesis of del(5q) MDS is lacking. Here we provide evidence that deficiency of miR-143 and miR-145 plays a role in clonal expansion of del(5q) MDS. We show that insulin-like growth factor 1 receptor (IGF-1R) is a direct target of both miR-143 and miR-145. Our data demonstrate that IGF-1R inhibition reduces proliferation and viability of del(5q) cells in vitro and in vivo, and that lenalidomide-resistant del(5q) MDS cells depleted of either TP53 or RUNX1 are sensitive to IGF-1R inhibition. Resistant del(5q) MDS-L cells, as well as primary MDS marrow cells, are also sensitive to targeting of IGF-1R-related dependencies in del(5q) MDS, which include the Abl and MAPK signaling pathways. This work thus provides potential new therapeutic avenues for lenalidomide-resistant del(5q) MDS.

DOI: https://doi.org/10.1038/s41375-025-02537-2
Cell Stem Cell. 2025 Feb 19. pii: S1934-5909(25)00012-8. [Epub ahead of print]

Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.

Indranil Singh, Daniel Fernandez-Perez, Pedro Sanchez Sanchez, Alejo E Rodriguez-Fraticelli.

  Cancer cells display wide phenotypic variation even across patients with the same mutations. Differences in the cell of origin provide a potential explanation, but traditional assays lack the resolution to distinguish clonally heterogeneous subsets of stem and progenitor cells. To address this challenge, we developed simultaneous tracking of recombinase activation and clonal kinetics (STRACK), a method to trace clonal dynamics and gene expression before and after the acquisition of cancer mutations. Using mouse models, we studied two leukemic mutations, Dnmt3a-R878H and Npm1c, and found that their effect was highly variable across different stem cell states. Specifically, a subset of differentiation-primed stem cells, which normally becomes outcompeted with time, expands with both mutations. Intriguingly, Npm1c mutations reversed the intrinsic bias of the clone of origin, with differentiation-primed stem cells giving rise to more primitive malignant states. Thus, we highlight the relevance of single-cell lineage tracing to unravel early events in cancer evolution and posit that different cellular histories carry distinct cancer phenotypic potential.

Keywords:  Dnmt3a; Npm1; cancer initiation; cell barcoding; cell of origin; clonal hematopoiesis; lineage tracing; myeloid leukemia; myeloid malignancies; single-cell

DOI:  https://doi.org/10.1016/j.stem.2025.01.012
Haematologica. 2025 Feb 27.

Molecular Predictors of Response and Survival in Patients with Relapsed/Refractory Acute Myeloid Leukemia following Venetoclax plus Hypomethylating Agent Therapy.

Isla M Johnson, Rimal Ilyas, Kristen McCullough, Aref Al-Kali, Hassan B Alkhateeb, Kebede H Begna, Abhishek Mangaonkar, Antoine Saliba, Mark R Litzow, William Hogan, Mithun Shah, Mrinal M Patnaik, Animesh Pardanani, Ayalew Tefferi, Naseema Gangat.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.286991
Blood. 2025 Feb 26. pii: blood.2024024636. [Epub ahead of print]

cMPL-Based Purification and Depletion of Human Hematopoietic Stem Cells: Implications for Pretransplant Conditioning.

Daisuke Araki, So Gun Hong, Nathaniel Seth Linde, Bryan Fisk, Neelam Redekar, Christi T Salisbury-Ruf, Allen Krouse, Theresa Engels, Justin Golomb, Pradeep K Dagur, Sumith R Panicker, Yogendra Kanthi, Diogo Magnani, Zhirui Wang, Andre Larochelle.

The thrombopoietin (TPO):cMPL signaling axis is a critical regulator of early hematopoiesis. However, the utility of cMPL as a standalone marker for identifying long-term repopulating hematopoietic stem cells (LT-HSCs) within the adult human CD34+ cell hematopoietic stem and progenitor cell (HSPC) population has not been validated. In this study, we established high cMPL surface expression as a defining feature of human LT-HSCs. Targeting the cMPL receptor facilitated the separation of human LT-HSCs from mature progenitors, a delineation not achievable with cKIT. Leveraging this finding, we explored the therapeutic potential of cMPL as a novel target for pre-transplant conditioning regimens. We developed a cMPL-targeting immunotoxin, demonstrating its ability to preferentially deplete host cMPLhigh LT-HSCs in murine xenograft models. Evaluation in rhesus macaques confirmed these findings and highlighted a favorable safety profile with rapid systemic clearance within 24 hours of administration. Proof-of-concept experiments validated the immunotoxin as a novel conditioning agent, enabling donor HSPC engraftment without the use of chemotherapy or irradiation. These findings advance our understanding of the molecular determinants of human hematopoiesis and underscore the potential of cMPL-targeting preparative regimens to improve therapeutic transplantation outcomes.

DOI: https://doi.org/10.1182/blood.2024024636
bioRxiv. 2025 Feb 12. pii: 2025.02.10.637540. [Epub ahead of print]

Posttranscriptional activity of the eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis.

Fang Zhou, Biljana Culjkovic-Kraljacic, Christian Bach, Li Feng, Yuta Mishima, Katherine L B Borden, Daniel G Tenen.

HoxA9, a homeodomain-containing transcription factor, is mis-expressed in over half of acute myeloid leukemia (AML) cases, and is associated with poor prognosis. Previous studies indicated that HoxA9 binds to the eukaryotic translation initiation factor eIF4E in primary specimens and that HoxA9 stimulated the RNA export and translation efficiency of selected RNAs via eIF4E. However, the relevance of this to its leukemogenic transformation capacity was unknown. Here, we used a double point mutation (HoxA9AA) to disrupt the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature. Surprisingly, the mutation dramatically increased AML latency from a median of 90 to 280 days and resulted in incomplete penetrance. Re-transplantation of bone marrow cells from leukemic animals demonstrated even more pronounced differences in disease kinetics and penetrance with all animals succumbing to disease by day 60 in the wildtype group, while some HoxA9AA mice never developed leukemia. Collectively, these findings uncover a novel, transcription-independent mechanism of HoxA9-driven leukemogenesis through eIF4E and positions eIF4E as a potential therapeutic target AML patients expressing high levels of HoxA9.
Key Points: A double point mutation in HoxA9 disrupted the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature.Eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis and is important for the maintenance of acute myeloid leukemia.

DOI: https://doi.org/10.1101/2025.02.10.637540
Exp Hematol. 2025 Feb 25. pii: S0301-472X(25)00038-4. [Epub ahead of print] 104747

Sex differences alter primitive progenitors in the C57BL/6 Tet2 knockout mouse model.

Samantha M Holmes, Christopher J Wells, Christine Hall, Amy J M McNaughton, Michael J Rauh, Sheela A Abraham.

  The precancerous expansion of hematopoietic cells, termed clonal hematopoiesis (CH), has been correlated to disease development and all-cause mortality. Despite multiple observations that hematopoietic stem cell and progenitors (HSPCs) are significantly affected by both sex and age, there remain few studies quantifying male and female HSPC populations in wild-type and transgenic Tet2 models over time. Here we determine that male mice (with a hematopoietic deficiency of Tet2 and control) have more Lin-Sca-1+c-kit+ (LSK) cells, that include multi-potent progenitor cells (MPP; LSK CD48-CD150-) and long-term hematopoietic stem cells (LT-HSC; LSK CD48-CD150+) compared to females. LT-HSC, MPP and progenitor populations were observed to possess equal male/female ratios in mice at 6 weeks of age; however, the LSK compartment was found most susceptible to sex-based effects in transgenic mice between 6 weeks and 4 months. In contrast, all differentiated progenitor populations analysed in mice were observed to be unaffected by sex between 6 weeks to 4 months. This study provides a comprehensive analysis of bone-sourced HSPCs in Tet2-deficient mouse models and reveals important sex and age considerations that must be taken into account when choosing mice for transgenic studies in C57BL/6 mice.

Keywords:  C57BL/6 mice; Clonal hematopoiesis; Mouse Models; Sex differences; Tet2

DOI:  https://doi.org/10.1016/j.exphem.2025.104747
Leukemia. 2025 Feb 27.

CD34+CD38- leukemia stem cells predict clinical outcomes in acute myeloid leukemia patients treated non-intensively with hypomethylating agents.

Tom Reuvekamp, Lok Lam Ngai, Daphne den Hartog, Jannemieke Carbaat-Ham, Mona M H E Fayed, Willemijn J Scholten, Tim R Mocking, Dana A Chitu, Thomas Pabst, Saskia K Klein, Georg Stussi, Laimonas Griskevicius, Dimitri Breems, Danielle van Lammeren-Venema, Rinske Boersma, Gert J Ossenkoppele, Arjan A van de Loosdrecht, Costa Bachas, Gerwin Huls, David C de Leeuw, Jacqueline Cloos.

DOI: https://doi.org/10.1038/s41375-025-02539-0
Leukemia. 2025 Feb 22.

STING mediates increased self-renewal and lineage skewing in DNMT3A-mutated hematopoietic stem/progenitor cells.

Jingru Huang, Jiaying Xie, Yin Wang, Mengyao Sheng, Yue Sun, Pingyue Chen, Shaoqin Rong, Dongrui Yin, Yuanxian Wang, Ping Zhu, Stefan K Bohlander, Guo-Liang Xu, Hai Gao, Dan Zhou, Yuheng Shi.

Somatic mutations in DNA methyltransferase 3 A (DNMT3A) are frequently observed in patients with hematological malignancies. Hematopoietic stem/progenitor cells (HSPCs) with mutated DNMT3A demonstrate increased self-renewal activity and skewed lineage differentiation. However, the molecular mechanisms underlying these changes remain largely unexplored. In this study, we show that Dnmt3a loss leads to the upregulation of endogenous retroviruses (ERVs) in HSPCs, subsequently activating the cGAS-STING pathway and triggering inflammatory responses in these cells. Both genetic and pharmacological inhibition of STING effectively corrects the increased self-renewal activity and differentiation skewing induced by Dnmt3a deficiency in mice. Notably, targeting STING showed inhibited acute myeloid leukemia (AML) development in a Dnmt3a-KO; Flt3-ITD AML model, comparable to AC220, an FDA-approved FLT3-ITD inhibitor. A patient-derived xenograft (PDX) model further demonstrated that targeting STING effectively alleviates the leukemic burden of DNMT3A-mutant AML. Collectively, our findings highlight a critical role for STING in hematopoietic disorders induced by DNMT3A mutations and propose STING as a potential therapeutic target for preventing the progression of DNMT3A mutation-associated leukemia.

DOI: https://doi.org/10.1038/s41375-025-02542-5
Nat Immunol. 2025 Feb 25.

Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.

Tomer Itkin, Sean Houghton, Ryan Schreiner, Yang Lin, Chaitanya R Badwe, Veronique Voisin, Alex Murison, Negar Seyedhassantehrani, Kerstin B Kaufmann, Laura Garcia-Prat, Gregory T Booth, Fuqiang Geng, Ying Liu, Jesus M Gomez-Salinero, Jae-Hung Shieh, David Redmond, Jenny Z Xiang, Steven Z Josefowicz, Cole Trapnell, Eric M Pietras, Joel A Spencer, Ross Levine, Wenbin Xiao, Lior Zangi, Brandon Hadland, John E Dick, Stephanie Z Xie, Shahin Rafii.

Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine.

DOI: https://doi.org/10.1038/s41590-025-02087-w
Blood. 2025 Feb 26. pii: blood.2024027217. [Epub ahead of print]

Venetoclax and Decitabine vs Intensive Chemotherapy as Induction for Young Patients with Newly Diagnosed AML.

Jing Lu, Shengli Xue, Ying Wang, Xuefeng He, Xiaohui Hu, Miao Miao, Yang Zhang, Zaixiang Tang, Jundan Xie, Xiaofei Yang, Mingzhu Xu, Yaoyao Shen, Feng Du, Qian Wu, Mengxing Xue, Yun Wang, Ailing Deng, Xueqing Dou, Yang Xu, Haiping Dai, Depei Wu, Suning Chen.

Venetoclax combined with hypomethylating agents is approved for frontline therapy in older/unfit acute myeloid leukemia (AML) patients. However, prospective data on this low intensity therapy in treatment-naive younger AML patients are lacking. This study investigated the efficacy and safety of venetoclax plus decitabine (VEN-DEC) as induction in untreated young fit AML patients in a randomized trial. Patients aged 18-59 years eligible for intensive chemotherapy were randomized 1:1 to receive VEN-DEC or IA-12 (idarubicin and cytarabine). All patients achieving CR/CRi underwent high-dose cytarabine consolidation. The primary endpoint was the composite complete remission rate (CRc) rate after induction therapy. Of 255 screened, 188 were enrolled and randomly assigned, with 94 in each group. In the intention-to-treat population, CRc was 89% (84/94) in the VEN-DEC group versus 79% (74/94) in IA-12 (non-inferiority P = 0.0021). MRD negativity after induction was 80% (67/84) versus 76% (56/74), respectively. VEN-DEC showed superior CRc in patients aged ≥40 years (91% vs. 75%), those with adverse risk (91% vs. 42%) or epigenetic mutations (91% vs. 67%) , but lower CRc in RUNX1::RUNX1T1 fusion cases (44% vs. 88%) compared to IA-12. Patients in the VEN-DEC group experienced fewer grade ≥3 infections (32% vs. 67%) and shorter severe thrombocytopenia duration (median 13 vs. 19 days, P < 0.001). At a median follow-up of 12.1 months, overall and progression-free survival were similar between groups. In conclusion, VEN-DEC demonstrated non-inferior response rates with superior safety over IA-12 in young AML patients. The trial was registered at ClinicalTrials.gov as #NCT05177731.

DOI: https://doi.org/10.1182/blood.2024027217
Blood Adv. 2025 Feb 24. pii: bloodadvances.2024015527. [Epub ahead of print]

MENIN MAINTENANCE THERAPY FOR ACUTE LEUKEMIA.

Olayinka Okeleji, David McCall, Amber Gibson, Miriam B Garcia, Cesar Nunez, Michael E Roth, Jeremy S Connors, Demetrios Petropoulos, Priti Tewari, Branko Cuglievan, Irtiza Naseer Sheikh.

DOI: https://doi.org/10.1182/bloodadvances.2024015527
J Clin Med. 2025 Feb 14. pii: 1254. [Epub ahead of print]14(4):

Use of Primary Prophylaxis with G-CSF in Acute Myeloid Leukemia Patients Undergoing Intensive Chemotherapy Does Not Affect Quality of Response.

Valeria Mezzanotte, Giovangiacinto Paterno, Ilaria Cerroni, Lucrezia De Marchi, Kristian Taka, Elisa Buzzatti, Flavia Mallegni, Elisa Meddi, Federico Moretti, Francesco Buccisano, Luca Maurillo, Raffaele Palmieri, Carmelo Gurnari, Adriano Venditti, Maria Ilaria Del Principe.

  Background/Objectives: The objective of our study was to evaluate the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) as primary prophylaxis in adult patients with acute myeloid leukemia (AML) undergoing intensive chemotherapy. Methods: We retrospectively analyzed 112 AML patients treated with intensive chemotherapy at Fondazione Policlinico Tor Vergata in Rome between January 2014 and March 2024. Patients were divided into G-CSF and non-G-CSF (nG-CSF) groups. We assessed the incidence of neutropenia, its severity and duration; duration of hospitalization and its costs; incidence of febrile neutropenia (FN) and septic shock; duration of antibiotic therapy (ABT) and antifungal therapy (AFT); complete remission (CR) rates; measurable residual disease (MRD) status; relapse rates; and outcomes. Results: G-CSF administration significantly reduced the duration of neutropenia (median 14 vs. 18 days, p < 0.05) and length of hospitalization (median 28 vs. 35 days, p < 0.05), in both induction and consolidation therapy. There were no significant differences in CR rates (73% vs. 67%, p = 0.64), MRD negativity achievement (52% vs. 48%, p = 0.68), leukemia relapse rates (43% vs. 62%, p = 0.14), or overall survival (OS) (median 16.7 vs. 12.3 months, p = 0.3) between G-CSF and nG-CSF groups. Thanks to a shorter hospitalization, the use of G-CSF led to €300,000 in savings over the last 4 years. Conclusions: Our findings support the safety of G-CSF in AML patients, demonstrating no adverse impact on treatment response. G-CSF abbreviated the duration of neutropenia and hospitalization, highlighting its potential clinical and cost-effective role in AML treatment.

Keywords:  acute myeloid leukemia; febrile neutropenia; granulocyte colony-stimulating factor

DOI:  https://doi.org/10.3390/jcm14041254
Clin Cancer Res. 2025 Feb 26. OF1-OF8

Cladribine Added to Idarubicin and Cytarabine as an Induction Regimen for Patients with De Novo Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Trial.

Xiang Zhang, Yue Han, Huiying Qiu, Miaoxinqi Han, Aining Sun, Shengli Xue, Zhengming Jin, Miao Miao, Ying Wang, Chengcheng Fu, Xiaowen Tang, Suning Chen, Caixia Li, Lian Bai, Zhihong Lin, Jun Chen, Haohao Han, Jia Chen, Depei Wu.

PURPOSE: To assess the efficacy and safety of an induction regimen composed of idarubicin, cytarabine, and cladribine (IAC) in patients with de novo acute myeloid leukemia (AML).
PATIENTS AND METHODS: Adult patients with newly diagnosed AML were randomized to the IAC group (cladribine 5 mg/m2/day for 5 days, idarubicin 8 mg/m2/day for 3 days, and cytarabine 100 mg/m2/day for 7 days) and the IA group (idarubicin 12 mg/m2/day for 3 days and cytarabine 100 mg/m2/day for 7 days) at a 1:2 ratio. The primary endpoint was complete remission (CR) after induction. Secondary endpoints included 2-year overall survival (OS), disease-free survival, and cumulative incidence of relapse.
RESULTS: A total of 618 adult patients with newly diagnosed AML were enrolled. The overall CR rate was 80.5% in the IAC group compared with 72.4% in the IA group (P = 0.029). The 2-year OS was 81.3% in the IAC group compared with 70.0% in the IA group (P = 0.011). Patients on the IAC regimen achieved a higher CR rate compared to those on the IA regimen, particularly in those with adverse risk (69.8% vs. 49.1%, P = 0.008), 2-year OS (80.1% vs. IA 58.1%, P = 0.014), and disease-free survival (78.8% vs. 51.3%, P = 0.009). In the subgroup of patients older than 45 years of age, the IAC regimen exerted better CR (77.1% vs. 62.6%, P = 0.033) and 2-year OS (74.7% vs. IA 55.0%, P = 0.019). There were no differences in chemotherapy-related toxicities between the groups.
CONCLUSIONS: Cladribine added to the IA regimen was safe and effective in de novo AML. Patients with adverse risk or those between 45 and 60 years of age might benefit significantly on both response and survival with the IAC regimen.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2437
Blood. 2025 Feb 27. pii: blood.2024027884. [Epub ahead of print]

Decoding functional hematopoietic progenitor cells in the adult human lung.

Catharina Conrad, Melia Magnen, Jessica Tsui, Harrison Jacob Wismer, Mohammad Naser, Urmila Venkataramani, Bushra Samad, Simon J Cleary, Longhui Qiu, Jennifer J Tian, Marco De Giovanni, Nicole Mende, Andrew D Leavitt, Emmanuelle Passegue, Elisa Laurenti, Alexis J Combes, Mark R Looney.

While the bone marrow is the main site of blood cell production in adults, rare pools of hematopoietic stem and progenitor cells have been found in extramedullary organs. In mice, we have previously shown that the lungs contain hematopoietic progenitor cells and is a site of platelet production. Here, in the adult human lung, we show that functional hematopoietic precursors reside in the extravascular spaces with a frequency similar to the bone marrow, and are capable of proliferation and engraftment in mice. The gene signature of pulmonary and medullary CD34+ hematopoietic progenitors indicates greater baseline activation of immune, megakaryocyte/platelet and erythroid-related pathways in lung progenitors. Spatial transcriptomics mapped blood progenitors in the lung to an alveolar interstitium niche with only a few cells identified in an intravascular location. In human blood samples collected for stem cell transplantation, CD34+ cells with a lung signature enriched the mobilized pool of hematopoietic stem cells. These results identify the lung as a pool for uniquely programmed blood stem and progenitor cells with the potential to support hematopoiesis in humans.

DOI: https://doi.org/10.1182/blood.2024027884
Blood. 2025 Feb 26. pii: blood.2024026934. [Epub ahead of print]

STING activation improves T-cell-engaging immunotherapy for acute myeloid leukemia.

Andreas Linder, Daniel Nixdorf, Niklas Kuhl, Ignazio Piseddu, Teng Teng Xu, Anne Verena Holtermann, Gunnar Kuut, Rebekka Elena Endres, Nora Philipp, Veit L Bücklein, Johann de Graaff, Thomas Carell, Sebastian Kobold, Roman Kischel, Veit Hornung, Marion Subklewe.

T-cell recruiting bispecific antibodies (BsAbs) are in clinical development for relapsed/refractory acute myeloid leukemia (AML). Despite promising results, early clinical trials have failed to demonstrate durable responses. We investigated whether activation of the innate immune system through stimulator of interferon genes (STING) can enhance target-cell killing by a BsAb targeting CD33 (CD33 BiTE® molecule, AMG 330). Indeed, we show that cytotoxicity against AML mediated by AMG 330 can be greatly enhanced when combined with the STING agonist 2',3'-cyclic GMP-AMP (cGAMP), or diABZI. We used in vitro cytotoxicity assays, immunoblotting, transcriptomic analyses, and extensive CRISPR-Cas9 knockout experiments to investigate the enhancing effect of a STING agonist on the cytotoxicity of AMG 330 against AML. Importantly, we validated our findings with primary AML cells, and in a xenograft AML model. Mechanistically, in addition to direct cytotoxic effects of STING activation on AML cells, activated T cells render AML cells more susceptible to STING activation through their effector cytokines interferon-gamma (IFNγ) and tumor necrosis factor (TNF), resulting in enhanced type I interferon production and induction of interferon-stimulated genes. This feeds back to the T cells, leading to a further increase in effector cytokines and an overall cytotoxic T-cell phenotype, contributing to the beneficial effect of cGAMP/diABZI in enhancing AMG 330-mediated lysis. We established a key role for IFNγ in AMG 330-mediated cytotoxicity against AML cells, and in rendering AML cells responsive to STING agonism. Here, we propose to improve the efficacy of CD33-targeting BsAbs by combining them with a STING agonist.

DOI: https://doi.org/10.1182/blood.2024026934
Haematologica. 2025 Feb 27.

Prognostic relevance of variant allelic frequency for treatment outcomes in patients with acute myeloid leukemia: a study by the Spanish PETHEMA registry.

Rafael Colmenares, Noemi Alvarez, Eva Barragan, Blanca Boluda, Maria J Larrayoz, Maria Carmen Chillon, Elena Soria-Saldise, Cristina Bilbao, Joaquin Sanchez-Garcia, Teresa Bernal, David Martinez-Cuadron, Cristina Gil, Josefina Serrano, Carlos Rodriguez-Medina, Juan Bergua, Jose A Perez-Simon, Maria Calbacho, Juan M Alonso-Dominguez, Jorge Labrador, Mar Tormo, Pilar Herrera-Puente, Cristina Martin-Arriscado, Andres Arroyo-Barea, Inmaculada Rapado, Claudia Sargas, Iria Vazquez, Maria J Calasanz, Teresa Gomez-Casares, Ramon Garcia-Sanz, Rebeca Rodriguez-Veiga, Joaquin Martinez-Lopez, Rosa Ayala, Pau Montesinos, Pethema Group.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.286311
Br J Haematol. 2025 Feb 23.

Identification of new candidate drugs in myelodysplastic syndromes with splicing factor mutations by transcriptional profiling and connectivity map analysis.

Tianyu Sun, Shalini Singh, Hayson Chenyu Wang, Juseong Lee, Hamid Dolatshad, Pak Leng Cheong, Douglas R Higgs, Jacqueline Boultwood, Andrea Pellagatti.

  We sought to identify new candidate drugs for repurposing to myelodysplastic syndromes (MDS). Connectivity map analysis was performed on gene expression signatures generated from bone marrow CD34+ cells of splicing factor mutant MDS patients. Celastrol and Withaferin A (WA), two top-ranking compounds identified, markedly inhibited proliferation, arrested the cell cycle and induced apoptosis in leukaemia cells. These compounds also inhibited the viability of primary bone marrow MDS cells. We showed that Celastrol and WA inhibit interleukin-1 receptor-associated kinase 4-mediated nuclear factor kappa-light-chain-enhancer of activated B cells signalling activation in splicing factor mutant MDS and leukaemia cells. Celastrol and WA may represent novel candidate drugs for the treatment of MDS.

Keywords:  MDS; connectivity map; drug repurposing; splicing factor mutations

DOI:  https://doi.org/10.1111/bjh.20026
Blood Adv. 2025 Feb 24. pii: bloodadvances.2024014570. [Epub ahead of print]

Gastrointestinal toxicity of Gemtuzumab Ozogamicin: Real-life data from the AMLCG, SAL and CELL study groups.

Ricarda Knabe, Philippe Muller, Christoph Schliemann, Maher Hanoun, Julia Marie Unglaub, Barbora Weinbergerová, Jiri Mayer, Carolin Krekeler, Stefan W Krause, Martin Kaufmann, Sabrina Kraus, Björn Steffen, Franziska Modemann, Marion Subklewe, Veit L Bücklein, Wolfgang G Kunz, Martina Rudelius, Michael von Bergwelt-Baildon, Katja Gutmair, Eva Hoster, Tobias Herold, Christoph Röllig, Karsten Spiekermann.

DOI: https://doi.org/10.1182/bloodadvances.2024014570
Cell Stem Cell. 2025 Feb 17. pii: S1934-5909(25)00013-X. [Epub ahead of print]

Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.

Zemin Song, Yali Cui, Lilan Xin, Ruijing Xiao, Jingjing Feng, Conghui Li, Zhinang Yin, Honghong Wang, Qiuzi Li, Mengxuan Wang, Baoyi Lin, Yiming Zhang, Ying Zhou, Li Huang, Yanli He, Xiaoqing Li, Xiaoyan Liu, Shangqin Liu, Fuling Zhou, Zheng Liu, Hai-Bing Zhou, Pingping Fang, Kaiwei Liang.

  Mitochondria are integrated within the cytoskeleton for structural integrity and functional regulation, yet the pathological exploitation of these interactions in cell fate decisions remains largely unexplored. Here, we identify a cytoskeleton-mitochondria remodeling mechanism underlying leukemic transformation by the core-binding factor subunit beta and smooth muscle myosin heavy-chain fusion (CBFβ-SMMHC). This chimera reconstructs a cytosolic filamentous cytoskeleton, inducing NMIIA phosphorylation and INF2-dependent filamentous actin (F-actin) assembly, which enhance cellular stiffness and tension, leading to calcium-mediated mitochondrial constriction, termed cytoskeletal co-option of mitochondrial constriction (CCMC). CCMC can also be triggered through diverse approaches independent of CBFβ-SMMHC, reconstructing a similar cytoskeleton and recapitulating acute myeloid leukemia (AML) with consistent immunophenotypes and inflammatory signatures. Notably, CCMC generates TOM20-PDH+mtDNA+ mitochondrial-derived vesicles that activate cGAS-STING signaling, with Sting knockout abrogating CCMC-induced leukemogenesis. Targeted inhibition of CCMC or STING suppresses AML propagation while sparing normal hematopoiesis. These findings establish CCMC as an intrinsic mechano-oncogenic process linking genetic mutations with cytoskeletal remodeling to oncogenic transformation, highlighting its promise as a therapeutic target.

Keywords:  CBFβ-SMMHC; CCMC; HSPCs; MDV; cGAS-STING signaling; cytoskeletal co-option of mitochondrial constriction; cytoskeleton; hematopoietic stem and progenitor cells; mitochondrial-derived vesicle

DOI:  https://doi.org/10.1016/j.stem.2025.01.013
Blood. 2025 Feb 26. pii: blood.2024027020. [Epub ahead of print]

NOTCH1 dimeric signaling is essential for T-cell leukemogenesis and leukemia maintenance.

Francesco Tamiro, Costanzo Padovano, Elisabetta De Santis, Serena Di Iasio, Francesca Delia Sansico, Valentina Canistro, Mattia Colucci, Chiara Di Nunzio, Gaja Bruno, Kashish Doshi, Angela Totaro, Eric Gu, Michele Santodirocco, Andrew P Weng, Vincenzo Giambra.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by an expansion of T-cell progenitors and DNA mutations that lead to an overactive NOTCH1 signaling in over 50% of T-ALL cases. Using synthetic models of human T-ALL, we report that NOTCH1 dimeric signaling was crucial for the leukemogenesis of human hematopoietic stem/progenitor cells (HSPCs) from cord blood. We also identified a Notch-dimerization-dependent gene signature, including HES4 transcription factor, which induced proliferative advantage in human HSPCs as well as in Notch-dimerization-dependent patient-derived xenografts (PDXs) of T-ALL. Interestingly, in human T-ALL cells, HES4 enforced the expression of D133p53 isoform with the concomitant block of pro-apoptotic p53 target genes and the induction of BCL2L1 gene expression and anti-apoptotic Bcl-xL protein. Additionally, through an integrated experimental approach including genetically modified cell lines, RNA/Chip-sequencing and single cell RNA-sequencing (scRNA-Seq) profiles of primary T-ALL samples, we revealed cell subsets with Notch-dimerization-dependent gene signature, which indirectly correlated with pro-apoptotic genes as well as directly associated with cell markers of poor clinical outcome in primary T-ALL samples. Taken together, these findings highlight the crucial role of NOTCH1 dimeric signaling in human T-cell leukemogenesis and T-ALL maintenance suggesting that a possible benefit can be obtained from a therapeutic strategy targeting NOTCH1-dimer signaling or its downstream effectors.

DOI: https://doi.org/10.1182/blood.2024027020
RSC Med Chem. 2025 Jan 30.

Discovery of selective, metabolically stable pyrazole-based FLT3 inhibitors for the treatment of acute myeloid leukemia.

Lorenza Destro, Valentina Crippa, Daniela Gabbia, Marco Roverso, Sara Bogialli, Paolo Zardi, Giovanni Marzaro, Luca Mologni, Alfonso Zambon.

Acute myeloid leukemia (AML) is the most prevalent form of acute leukemia in adults, representing a substantial medical need, as the standard of care has not changed for the past two decades, and the long-term outcome remains dismal for a large fraction of patients. Approximately 30% of AMLs carry activating mutations of the FLT3 kinase. Unfortunately, single-agent FLT3 inhibitor therapy has met limited clinical efficacy, underscoring a strong rationale for the development of more selective and more potent inhibitors. Here we present the design, synthesis and biological evaluation of a series of biphenyl substituted pyrazoyl-ureas, an underexplored scaffold in medicinal chemistry, as novel FLT3 inhibitors with a putative type II binding mode. Optimized compounds show nanomolar activity against isolated FLT3 (230 nM for compound 10q) and on FLT3-driven cell lines (280 nM and 18 nM for compound 10q against MV4.11 and MOLM-14 cells respectively), with no toxicity against control cell lines, limited metabolism in human microsomes and a reliable SAR; furthermore, profiling of compound 10q against a panel of kinases highlights c-Kit as the only other hit. Overall, we show that the series has a narrow selectivity profile and metabolic stability, and the mode of action of the inhibitors through FLT3 is confirmed by strong suppression of FLT3 and STAT5 phosphorylation.

DOI: https://doi.org/10.1039/d4md00956h
Sci Transl Med. 2025 Feb 26. 17(787): eadl6758

Single-cell analysis of aplastic anemia reveals a convergence of NK and NK-like CD8+ T cells with a disease-associated TCR signature.

Sofie Lundgren, Jani Huuhtanen, Mikko Keränen, Xingmin Feng, Bhavisha A Patel, Georgina L Ryland, Lucy C Fox, Carlos Bravo-Perez, Michael Clemente, Cassandra Kerr, Gunilla Walldin, Olli Dufva, Yoshitaka Zaimoku, Tiina Tuononen, Mikko Myllymäki, Freja Ebeling, Emmi Jokinen, Markus Heinonen, Tiina Kasanen, Jay Klievink, Hanna Lähteenmäki, Taina Jaatinen, Sari Kytölä, Sanna Siitonen, Alina Dulau-Florea, Raul Braylan, Merja Heinäniemi, Shinji Nakao, Eva Hellström-Lindberg, Jaroslaw P Maciejewski, Piers Blombery, Neal S Young, Harri Lähdesmäki, Satu Mustjoki.

Immune aplastic anemia (AA) is a life-threatening bone marrow failure disorder driven by an autoimmune T cell attack against hematopoietic stem and progenitor cells (HSPCs). However, the exact autoantigen targets and role of other immune cells in the pathogenesis of AA are unknown. Here, we analyzed a cohort of 218 patients with AA using single-cell RNA and T cell receptor (TCR) αβ sequencing, TCRβ sequencing, flow cytometry, and plasma cytokine profiling. We identified natural killer (NK) cells and CD8+ terminally differentiated effector T (TEMRA) cells expressing NK receptors with AA-associated TCRβ motifs as the most dysregulated immune cell populations in AA bone marrow. Functional coculture experiments using primary HSPCs and immune cells showed that NK cells cannot kill HSPCs alone but may sensitize HSPCs to CD8+ T cell-mediated killing through production of interferons. Furthermore, HSPCs induced activation of T cell clones with CD8+ TEMRA NK-like phenotype in coculture. Our results reveal a convergent phenotype of innate and adaptive immune cells that may drive AA.

DOI: https://doi.org/10.1126/scitranslmed.adl6758
Bone Marrow Transplant. 2025 Feb 26.

Long-term patient-reported outcomes following allogeneic hematopoietic cell transplantation.

Sina Alexandra Beer, Johanna Blättel, Kristina Reuß, Claus-Philipp Maier, Christoph Faul, Wichard Vogel, Wolfgang Bethge, Claudia Lengerke.

Therapeutic progress has improved the overall survival of patients treated with allogeneic hematopoietic cell transplantation (alloHCT). Thus, the impact on quality of life (QoL) becomes increasingly relevant. However, QoL is not monitored regularly in clinical practice, and most trials stop QoL assessments early post-alloHCT, missing long-term dynamics. To address this knowledge gap, we conducted a cross-sectional survey of 214 adult alloHCT recipients (average age 53 y, 42.5% female, median follow-up 56 months) to evaluate QoL using patient-reported outcome measurements (PROMs), spanning a period from 30 days to over 10 years post-transplant. Participants completed the EORTC QLQ-C30 and FACT-BMT at a single follow-up timepoint to investigate QoL-related factors. Comparing long-term follow-up patients (beyond year 3, n = 125) with short-term follow-up patients (day 30 to month 12, n = 89) shows significantly better long-term QoL outcomes (P = 0.016). However, PROM symptom scales indicate moderate fatigue and insomnia rates in long-term survivors. Better QoL was associated with male gender, lower ECOG, RIC conditioning, no relapse, no ongoing immunosuppression and full-time work. Summarized, while we observe encouraging long-term outcomes, our data suggest that QoL recovery remain highly individual. We strongly recommend the use of PROMs to enhance our understanding of long-term survivorship post-alloHCT.

DOI: https://doi.org/10.1038/s41409-025-02540-2
Leukemia. 2025 Feb 25.

Comparison of recognition of symptom burden in MPN between patient- and physician-reported assessment - an intraindividual analysis by the German Study Group for MPN (GSG-MPN).

German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Myeloproliferative neoplasms (MPN) are associated with a variety of symptoms that severely impact patients' quality of life and ability to perform daily activities. Recent studies showed differences in the perception of physician- versus patient-reported symptom burden. However, studies directly comparing patient- and physician-reported ratings are lacking. Here, a retrospective analysis on symptom burden of 3979 MPN patients of the Bioregistry of the German Study Group for MPN was conducted to intra-individually compare physician and patient reports collected at the same time. Cohen's kappa was calculated to assess the degree of agreement between patient and physician reports. Factors influencing baseline symptom severity were identified using linear regression and adjusted Cox models were calculated to investigate the effect of symptom burden on survival. MPN patients had a high symptom burden, which neither decreased over time nor upon cytoreductive therapy. All symptoms were more frequently reported by patients compared to physicians. Agreement remained low and only slightly improved when considering a higher threshold for patient symptom severity. Patients with severe symptom burden had inferior survival compared to patients with less severe symptoms. Assessment of symptom burden in MPN is therefore insufficient and patient-reported outcome tools need to be implemented into clinical routine.

DOI: https://doi.org/10.1038/s41375-025-02524-7
Haematologica. 2025 Feb 27.

Maintenance therapy with oral decitabine plus cedazuridine after allogeneic stem cell transplantation for myelodysplastic syndrome.

Portia Smallbone, Terri Lynn Shigle, Oren Paslovsky, Chitra Hosing, Amin Alousi, Qaiser Bashir, Yosra Aljawai, Jeremy Ramdial, Uday Popat, Richard Champlin, Elizabeth J Shpall, Betül Oran.

Disease relapse remains the primary challenge for patients undergoing allogeneic transplantation (HSCT) for myelodysplastic syndrome (MDS). Maintenance therapies with hypomethylating agents are under investigation for use in mitigating relapse in high-risk patients. In this retrospective study, we assessed the safety and efficacy of oral decitabinecedazuridine maintenance in 18 high-risk MDS patients post-HSCT. 66.7% (n=12) received decitabine-cedazuridine (35/100mg) on days 1 and 3, while 33.3% (n=6) received therapy on days 1-3. Patients completed a median of six treatment cycles (range; 1-20), with one third of patients completing all planned cycles. No unexpected adverse events were observed, with the primary toxicity being myelosuppression. Grade 1-2 upper respiratory tract infections occurred in 4 patients, and fungal pneumonia in one patient. Overall, patients achieved a median 2-year relapse-free survival (RFS) of 66.7% (95% CI, 40.4-83.4%) and 2-year overall survival of 72.2% (95% CI, 45.6%-87.4%), with relapses occurring predominantly in TP53- mutated cases. Prospective clinical trials are essential to confirm the best tolerated dose with potential to improve transplant outcomes.

DOI: https://doi.org/10.3324/haematol.2024.287177
Blood. 2025 Feb 26. pii: blood.2024026581. [Epub ahead of print]

A First-in-Class JAK/ROCK Inhibitor, Rovadicitinib, for Glucocorticoid-Refractory or -Dependent Chronic GVHD.

Yanmin Zhao, Yi Luo, Jimin Shi, Shunqing Wang, Caixia Xia Wang, Erlie Jiang, Chen Liang, Xiaoyu Zhu, Xuejun Zhang, Fankai Meng, Hua Jin, Yeqian Zhao, Jian Yu, Xiaoyu Lai, Lizhen Liu, Huarui Fu, Yishan Ye, Congxiao Zhang, Tao Wang, Lifan Tu, Xunqiang Wang, He Huang.

Rovadicitinib (TQ05105) is a novel, oral dual JAK1/2 and ROCK1/2 inhibitor targeting inflammatory and fibrotic components of chronic graft-versus-host disease (cGVHD). We aimed to evaluate the safety and efficacy of rovadicitinib for glucocorticoid-refractory or -dependent cGVHD. This phase 1b/2a, multicenter, open-label study (NCT04944043) enrolled patients with moderate or severe glucocorticoid-refractory or -dependent cGVHD. The study followed a 3+3 design with two escalating doses (rovadicitinib 10 and 15 mg twice daily) and a dose expansion cohort. Primary endpoints included safety and recommended phase 2 dose (RP2D); the best overall response (BOR) was the key secondary endpoint. Forty-four patients were enrolled, with 29 in the 10 mg twice-daily cohort and 15 in the 15 mg twice-daily cohort. Rovadicitinib was well tolerated without dose-limiting toxicity at both dosages, and no rovadicitinib-related AEs led to discontinuation. The most prevalent hematological AE was anemia (38.6%), with grade ≥ 3 of 4.6%. The RP2D was 10 mg twice daily. The BOR was 86.4% (95% confidence interval [CI], 72.6-94.8), with no difference between the two dosage cohorts. Besides, BOR achieved 72.7% (8/11) in the steroid-refractory cohort and 90.9% (30/33) in the steroid-dependent cohort. All affected organs exhibited responses regardless of prior therapy. The failure-free survival rate was 85.2% (95% CI, 64.5-94.3) at 12 months. Rovadicitinib treatment reduced the corticosteroid dose in 88.6% of patients. cGVHD-related symptoms were improved in 59.1% of patients. Rovadicitinib has favorable tolerability and notable clinical response rates, ameliorating the quality of life and reducing corticosteroid dose requirements in patients with glucocorticoid-refractory or -dependent cGVHD.

DOI: https://doi.org/10.1182/blood.2024026581
Nature. 2025 Feb 26.

Systems-level design principles of metabolic rewiring in an animal.

Xuhang Li, Hefei Zhang, Thomas Hodder, Wen Wang, Chad L Myers, L Safak Yilmaz, Albertha J M Walhout.

The regulation of metabolism is vital to any organism and can be achieved by transcriptionally activating or repressing metabolic genes1-3. Although many examples of transcriptional metabolic rewiring have been reported4, a systems-level study of how metabolism is rewired in response to metabolic perturbations is lacking in any animal. Here we apply Worm Perturb-Seq (WPS)-a high-throughput method combining whole-animal RNA-interference and RNA-sequencing5-to around 900 metabolic genes in the nematode Caenorhabditis elegans. We derive a metabolic gene regulatory network (mGRN) in which 385 perturbations are connected to 9,414 genes by more than 110,000 interactions. The mGRN has a highly modular structure in which 22 perturbation clusters connect to 44 gene expression programs. The mGRN reveals different modes of transcriptional rewiring from simple reaction and pathway compensation to rerouting and more complex network coordination. Using metabolic network modelling, we identify a design principle of transcriptional rewiring that we name the compensation-repression (CR) model. The CR model explains most transcriptional responses in metabolic genes and reveals a high level of compensation and repression in five core metabolic functions related to energy and biomass. We provide preliminary evidence that the CR model may also explain transcriptional metabolic rewiring in human cells.

DOI: https://doi.org/10.1038/s41586-025-08636-5
Br J Haematol. 2025 Feb 22.

Real-world evidence of pegcetacoplan in patients with paroxysmal nocturnal haemoglobinuria: A nationwide Italian study.

Elisabetta Metafuni, Filippo Achille Brioschi, Andrea Patriarca, Claudia Leoni, Giorgia Battipaglia, Daniela Carlino, Annalisa Condorelli, Valeria Di Giacomo, Sarah Marktel, Maria Antonietta Marzilli, Maurizio Miglino, Esther Natalie Oliva, Antonella Sau, Alessandra Ricco, Grazia Sanpaolo, Annarita Trolese, Anna Paola Iori, Simona Sica, Wilma Barcellini, Bruno Fattizzo.

In this study, we collected real-world evidence on the use of pegcetacoplan among 22 Italian patients with paroxysmal nocturnal haemoglobinuria showing suboptimal response to anti-C5 treatments eculizumab and ravulizumab. Most patients exhibited a complete or good response as per the criteria of the European Bone Marrow Transplant group (Risitano et al. Front Immunol 2019) and median haemoglobin improvement from baseline was +3.6 g/dL. During the 6-month follow-up, 27% of patients displayed a breakthrough haemolytic event mainly managed with supportive treatment. No thromboses occurred.

DOI: https://doi.org/10.1111/bjh.20025