bims-tremyl 2025-03-30 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2025–03–30
twenty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Reducing clinical trial eligibility barriers for patients with MDS: an icMDS position statement.
BH3 mimetics augment cytotoxic T cell killing of acute myeloid leukemia via mitochondrial apoptotic mechanism.
XPO1-dependency of DEK::NUP214 leukemia.
TP53-Mutated Acute Myeloid Leukemia and Blast Phase Myeloproliferative Neoplasm: Distinct Mutation Leads to Poorer Prognosis.
Optimization of allogeneic hematopoietic cell transplantation for patients with myelofibrosis treated with ruxolitinib: eligibility, best practices, and improving transplant outcomes.
Clinicopathologic Characteristics and Prognostic Profile of Chronic Myeloid Neoplasms With Somatic NF1 Mutations in Adult Patients.
Allogeneic Haematopoietic Stem Cell Transplantation Using Reduced-Intensity Fludarabine, Busulfan and Anti-T-Lymphocyte Globulin With Strategic Donor Lymphocyte Infusion in Older Patients With Myeloid Malignancy.
Hematological phenotypes in GATA2 deficiency syndrome arise from aging maladaptation to proliferation and somatic events.
Use of machine learning techniques to predict poor survival after hematopoietic cell transplantation for myelofibrosis.
Tracking clusterin expression in hematopoietic stem cells reveals their heterogeneous composition across the lifespan.
A phase 1 study of durvalumab as monotherapy or combined with tremelimumab with or without azacitidine in patients with myelodysplastic syndrome.
Disease Phenotype Significantly Influences the Outcome After Discontinuation of Ruxolitinib in Chronic Phase Myelofibrosis.
Functional Role of Fatty Acid Synthase for Signal Transduction in Core-Binding Factor Acute Myeloid Leukemia with an Activating c-Kit Mutation.
Atypical chronic myeloid leukemia: from cytology to molecular characterization.
Allo-HCT refined ELN 2022 risk classification: validation of the Adverse-Plus risk group in AML patients undergoing allogeneic hematopoietic cell transplantation within the Spanish Group for Hematopoietic Cell Transplantation (GETH-TC).
Low-risk MDS-A spotlight on precision medicine for SF3B1-mutated patients.
Real World Management of Cytopenias and Infections in Patients With Myelofibrosis Treated With Ruxolitinib.
Germ line JAK2 variants and hereditary blood cancers.
Cancer-associated SF3B1 mutation K700E causes widespread changes in U2/branchpoint recognition without altering splicing.
Two distinct fetal-type signatures characterize juvenile myelomonocytic leukemia.
Bemcentinib as monotherapy and in combination with low-dose cytarabine in acute myeloid leukemia patients unfit for intensive chemotherapy: a phase 1b/2a trial.
What is radiation-induced acute myeloid leukaemia/can it be accurately identified?
Cytogenetic abnormalities in polycythemia vera: phenotypic correlates and prognostic relevance in 669 informative cases.
Elderberry wine and promyelocytic leukemia.
SUMOylation facilitates the stability of BCR-ABL to promote chronic myeloid leukemia progression.
CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant.

Blood. 2025 Mar 27. 145(13): 1369-1381

Reducing clinical trial eligibility barriers for patients with MDS: an icMDS position statement.

Uma Borate, Kelly Pugh, Allyson Waller, Rina Li Welkie, Ying Huang, Jan Philipp Bewersdorf, Maximilian Stahl, Amy E DeZern, Uwe Platzbecker, Mikkael A Sekeres, Andrew H Wei, Rena J Buckstein, Gail J Roboz, Michael R Savona, Sanam Loghavi, Robert P Hasserjian, Pierre Fenaux, David A Sallman, Christopher S Hourigan, Matteo Giovanni Della Porta, Stephen Nimer, Richard F Little, Valeria Santini, Fabio Efficace, Justin Taylor, Guillermo Garcia-Manero, Olatoyosi Odenike, Tae Kon Kim, Stephanie Halene, Rami S Komrokji, Elizabeth A Griffiths, Peter L Greenberg, Mina L Xu, Zhuoer Xie, Rafael Bejar, Guillermo F Sanz, Mrinal M Patnaik, Maria Figueroa, Hetty E Carraway, Omar Abdel-Wahab, Daniel Starczynowski, Eric Padron, Jacqueline Boultwood, Steven Gore, Naval G Daver, Jane E Churpek, Ravindra Majeti, John M Bennett, Alan F List, Andrew M Brunner, Amer M Zeidan.

ABSTRACT: Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.

DOI: https://doi.org/10.1182/blood.2023023717
Cell Death Discov. 2025 Mar 26. 11(1): 120

BH3 mimetics augment cytotoxic T cell killing of acute myeloid leukemia via mitochondrial apoptotic mechanism.

Kapil Saxena, Shao-Hsi Hung, Esther Ryu, Shailbala Singh, Qi Zhang Tatarata, Zhihong Zeng, Zhe Wang, Marina Y Konopleva, Cassian Yee.

Adoptive cell therapy (ACT) can address an unmet clinical need for patients with relapsed/refractory acute myeloid leukemia (AML), but its effect is often modest in the setting of high tumor burden. In this study, we postulated that strategies to lower the AML apoptotic threshold will augment T cell killing of AML cells. BH3 mimetics, such as venetoclax, are a clinically approved class of compounds that predispose cells to intrinsic apoptosis by inhibiting anti-apoptotic mitochondrial proteins. We explored the anti-leukemic efficacy of BH3 mimetics combined with WT1-specific CD8+ T cells on AML cell lines and primary samples from patients with a diverse array of disease characteristics to evaluate if lowering the cellular apoptotic threshold via inhibition of anti-apoptotic mitochondrial proteins can increase leukemic cell sensitivity to T cell therapy. We found that the combination approach of BH3 mimetic and CD8+ T cells led to significantly increased killing of established AML lines as well as of adverse-risk primary AML leukemic blast cells. In contrast to the hypothesis that enhanced killing would be due to combined activation of the intrinsic and extrinsic apoptotic pathways, our data suggests that CTL-mediated killing of AML cells was accomplished primarily through activation of the intrinsic/mitochondrial apoptotic pathway. This highly effective combinatorial activity due to convergence on the mitochondrial apoptotic pathway was conserved across multiple AML cell lines and primary samples, suggesting that mitochondrial priming may represent a novel mechanism of optimizing adoptive cell therapy for AML patients.

DOI: https://doi.org/10.1038/s41420-025-02375-2
Leukemia. 2025 Mar 27.

XPO1-dependency of DEK::NUP214 leukemia.

Fiorella Charles Cano, Arnold Kloos, Rucha Y Hebalkar, Thomas Plenge, Robert Geffers, Hanna Kirchhoff, Nadine Kattre, Kerstin Görlich, Guntram Büsche, Halyna R Shcherbata, Michaela Scherr, Konstanze Döhner, Razif Gabdoulline, Michael Heuser.

The nuclear export protein XPO1 interacts with nucleoporin 214 (NUP214) and has been implicated in the pathogenesis of SET::NUP214 acute myeloid leukemia (AML). We evaluated DEK::NUP214 (DN), characterizing a distinct AML entity, for its dependency on XPO1 in human AML models. Deletion of XPO1 in DN-positive FKH-1 cells revealed a strong dependency on XPO1. Pharmacologic inhibition of XPO1 by the second-generation selective inhibitor of nuclear export, eltanexor, in primary human and FKH-1 cells reduced XPO1 expression, disrupted co-localization of XPO1 and DN, and induced apoptosis and cell cycle arrest. Functionally, XPO1 and DN co-localized at chromatin, and this co-localization was strongly reduced by XPO1 inhibition. Loss of chromatin binding resulted in downregulation of DN target genes and pathways related to cell cycle and self-renewal. Eltanexor treatment of a patient-derived DN-AML xenograft model disrupted leukemia development, showing molecular clearance in bone marrow after a median of 377 days in eltanexor-treated mice, while control mice succumbed after a median of 244 days. In summary, XPO1 stabilizes DN at chromatin to allow the activation of its oncogenic gene signature, while targeting XPO1 treats leukemia successfully in vivo. These findings establish XPO1 as a molecular target in DEK::NUP214 AML.

DOI: https://doi.org/10.1038/s41375-025-02570-1
Eur J Haematol. 2025 Mar 28.

TP53-Mutated Acute Myeloid Leukemia and Blast Phase Myeloproliferative Neoplasm: Distinct Mutation Leads to Poorer Prognosis.

Dong Chen, Miguel Cantu, Alexa Siddon, Olga K Weinberg.

  Patients with TP53 mutations in acute myeloid leukemia (AML) and blast phase myeloproliferative neoplasms (MPN-BP) experience similar poor clinical outcomes. A retrospective analysis of 39 patients with TP53 mutations (23 with AML and 16 with MPN-BP) revealed comparable mutation patterns associated with prognostic significance. A total of 47 distinct TP53 mutations were identified, including seven patients with multiple mutations. Based on clinical outcomes, we propose a two-tiered risk stratification for TP53-mutated AML and MPN-BP. The high-risk group mutations, such as splice site variants in Intron 4 (especially c.376), missense mutations in Exon 5 (notably p.R175H), and mutations in the oligomerization domain (OD), were associated with, particularly, worse overall survival (OS < 3 months). Conversely, single missense mutations in Exons 6 and 7 (notably p.Y220C, p.R248N, p.R248Q, and p.R248W), and mutations in the transactivation domain (TAD), constituted a low-risk group and were associated with relatively better prognosis (median OS: 10.15 months for the low-risk group vs. 1.3 months for the high-risk group, p < 0.0001). These findings support the hypothesis that distinct TP53 mutations can lead to varying cellular effects, therapeutic responses, and clinical outcomes. Consequently, acute myeloid neoplasms (AML and MPN-BP) harboring certain TP53 mutations may exhibit increased aggressiveness compared to other TP53 mutants, underscoring the need for prioritized clinical research and therapeutic targeting.

Keywords:  AML‐TP53; MPN‐BP‐TP53; TP53 mutation; acute myeloid leukemia with mutated TP53; blast phase myeloproliferative neoplasm with mutated TP53

DOI:  https://doi.org/10.1111/ejh.14421
Ann Hematol. 2025 Mar 22.

Optimization of allogeneic hematopoietic cell transplantation for patients with myelofibrosis treated with ruxolitinib: eligibility, best practices, and improving transplant outcomes.

Sarah A Wall, Roni Tamari, Zachariah DeFilipp, Gabriela S Hobbs.

  Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for myelofibrosis (MF), and current guidelines recommend assessing all patients with MF for eligibility. Several patient- and disease-specific factors impact transplantation outcomes, and timely assessment of potential transplant candidates is key to optimizing post-HCT outcomes. The role of HCT in the treatment of MF continues to evolve, with the adoption of newer and safer approaches, enhanced donor availability, use of reduced-intensity conditioning, improvements in graft-versus-host disease (GVHD) prophylaxis and treatment, and greater understanding of high-risk clinical and molecular features of the disease. These developments highlight the importance of early and ongoing assessment throughout the MF disease course to optimize eligibility and consideration for HCT. Ruxolitinib is approved for first-line treatment of intermediate- or high-risk MF, and emerging data have clarified the important role of ruxolitinib in not only optimizing clinical status before HCT but also mitigating and treating post-HCT complications in patients with MF, notably acute and chronic GVHD and relapse. Here we review strategies for optimizing clinical outcomes in patients considered for and undergoing HCT for MF treated with ruxolitinib. We discuss strategies for appropriate patient and donor selection, optimization of ruxolitinib therapy in the pre- and peri-HCT periods, choice of conditioning regimen, GVHD prophylaxis, post-HCT management of GVHD, continued monitoring for MF relapse, and the role of post-HCT ruxolitinib maintenance to reduce risks of GVHD and disease relapse.

Keywords:  Janus kinase; Myelofibrosis; Myeloproliferative neoplasm; Ruxolitinib

DOI:  https://doi.org/10.1007/s00277-025-06270-9
Eur J Haematol. 2025 Mar 28.

Clinicopathologic Characteristics and Prognostic Profile of Chronic Myeloid Neoplasms With Somatic NF1 Mutations in Adult Patients.

Hamza Tariq, Margarita Loxas, Mir B Alikhan, Juehua Gao, Xinyan Lu, Qing Ching Chen, Yi-Hua Chen, Jessica K Altman, Lawrence J Jennings, Madina Sukhanova.

   OBJECTIVES: The clinicopathologic and prognostic features of somatic NF1 mutations have been well studied in pediatric myeloid neoplasms and adult acute myeloid leukemia (AML) but not in adult chronic myeloid neoplasms (CMNs), including myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs).
METHODS: A retrospective review was performed to identify adult patients diagnosed with NF1-mutated CMNs between 1/2010 and 8/2023. Patients with NF1 wildtype (NF1-WT) CMNs concurrently diagnosed during the same time were used as a comparative group. Clinicopathologic and genetic characteristics and overall survival (OS) were compared between the two groups.
RESULTS: A total of 36 NF1-mutated CMNs were identified (4.7% of all CMNs), including 19 MDS, 4 MPNs, and 13 MDS/MPNs (all CMML). NF1-mutated CMMLs showed significantly higher absolute monocyte counts (AMC), more frequent complex karyotypes, and higher frequencies of SRSF2 and KRAS mutations compared to NF1-WT CMMLs. NF1-mutated MDS also showed significantly higher AMC, lower frequency of SF3B1, and higher frequencies of SRSF2 and KRAS mutations compared to NF1-WT MDS. The OS of NF1-mutated CMNs was significantly inferior to NF1-WT CMNs (median survival: 2.05 vs. 4.8 years; log-rank p = 0.03).
CONCLUSIONS: Adult CMNs with mutated NF1 show higher AMC, high-risk molecular cytogenetic features, and inferior survival. Therefore, testing for NF1 mutations could be considered part of risk assessment for patients with CMNs.

Keywords:  NF1; adult patients; chronic myeloid neoplasms

DOI:  https://doi.org/10.1111/ejh.14419
Eur J Haematol. 2025 Mar 27.

Allogeneic Haematopoietic Stem Cell Transplantation Using Reduced-Intensity Fludarabine, Busulfan and Anti-T-Lymphocyte Globulin With Strategic Donor Lymphocyte Infusion in Older Patients With Myeloid Malignancy.

Chris Armstrong, Eibhlin Conneally, Catherine Flynn, Paul Browne, Mairead Ni Chonghaile, Carmel Ann Galligan, Hayley Foy-Stones, Nicola Gardiner, Greg Lee, Nina Orfali.

  Fludarabine, busulfan, and anti-T-lymphocyte globulin (FLUBU3+ATLG) reduced-intensity conditioning is an established preparative regimen for allogeneic haematopoietic stem cell transplantation in older patients with myeloid malignancy. We examined its modern-day performance in 175 sequentially treated patients on our national programme. Overall survival was 72.4% at 2 years (95% CI 64.6%-78.6%) with a cumulative incidence of non-relapse mortality of 11%. The cumulative 2-year relapse incidence was 27% (95% CI 22.8%-37.6%) and was partially ameliorated by chronic graft-versus-host disease (HR 0.35, 95% CI 0.12-0.98, p = 0.02). Mixed donor chimerism was observed in 51.5% beyond day 90, but relapse was significantly reduced in these patients by adopting a pre-emptive donor lymphocyte infusion (DLI) strategy (HR 0.22, 95% CI 0.07-0.69, p = 0.005). The use of DLI as part of post-relapse salvage was also effective, with an improved median survival duration of 6 months in recipients (HR 0.43, 95% CI 0.18-0.98, p = 0.01). Outcomes in patients > 65 years and a limited cohort > 70 years are encouraging and compare favourably to published survival results using alternate reduced-intensity regimens. FLUBU3+ATLG, supported by modern supportive care and a pre-emptive DLI strategy, is well tolerated by older patients across a spectrum of myeloid disease with modest toxicity and favourable long-term outcomes.

Keywords:  DLI; RIC; conditioning; myeloid; transplantation

DOI:  https://doi.org/10.1111/ejh.14417
Blood Adv. 2025 Mar 26. pii: bloodadvances.2024015106. [Epub ahead of print]

Hematological phenotypes in GATA2 deficiency syndrome arise from aging maladaptation to proliferation and somatic events.

Juncal Fernandez-Orth, Cansu Koyunlar, Julia Miriam Weiss, Emanuele Gioacchino, Hans W J de Looper, Geoffroy Andrieux, Mariette Ter Borg, Joke Zink, Irene Gonzalez Menendez, Remco Hoogenboezem, Baris Ismail Yigit, Kirsten Gussinklo, Roger Mulet-Lazaro, Charlotte Wantzen, Sophie Pfeiffer, Christian Molnar, Eric Bindels, Sheila Bohler, Mathijs Arnoud Sanders, Leticia Quintanilla-Martinez, Marcin W Wlodarski, Melanie Boerries, Ivo P Touw, Charlotte Niemeyer, Miriam Erlacher, Emma de Pater.

The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the GATA2 gene drive severe hematologic abnormalities and are associated with an increased risk of myelodysplastic syndromes and acute myeloid leukemia; however, the mechanisms underlying the pathophysiology of GATA2 deficiency remain still unclear. We developed two different mouse models that are based on serial and limiting donor cell transplantation of (aged) GATA2 haploinsufficient cells and mirror the symptoms of GATA2 deficiency. Similar to what has been observed in patients, our models show that GATA2 haploinsufficiency leads to B lymphopenia, monocytopenia, lethal bone marrow failure (BMF), myelodysplasia and lymphoblastic leukemia. Leukemia arises exclusively as a result of BMF, driven by somatic aberrations and accompanied by increased Myc target expression and genomic instability. These findings were confirmed in human GATA2+/- K562 cell lines showing defects in cytokinesis and are in line with the fact that monosomy 7 and trisomy 8 are frequent events in patients with MDS.

DOI: https://doi.org/10.1182/bloodadvances.2024015106
Blood. 2025 Mar 27. pii: blood.2024027287. [Epub ahead of print]

Use of machine learning techniques to predict poor survival after hematopoietic cell transplantation for myelofibrosis.

Juan Carlos Hernandez-Boluda, Adrian Mosquera Orgueira, Luuk Gras, Linda Koster, Joe Tuffnell, Nicolaus Kröger, Massimiliano Gambella, Thomas Schroeder, Marie Robin, Katja Sockel, Jakob R Passweg, Igor Wolfgang Blau, Ibrahim Yakoub-Agha, Ruben Van Dijck, Matthias Stelljes, Henrik Sengeloev, Jan Vydra, Uwe Platzbecker, Moniek Dewitte, Frédéric Baron, Kristina Carlson, Javier Alberto Rojas Martínez, Carlos Pérez Míguez, Davide Crucitti, Kavita Raj, Joanna Drozd-Sokolowska, Giorgia Battipaglia, Nicola Polverelli, Tomasz Czerw, Donal P McLornan.

With the incorporation of effective therapies for myelofibrosis (MF), accurately predicting outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) is crucial for determining the optimal timing for this procedure. Using data from 5,183 MF patients who underwent first allo-HCT between 2005 and 2020 at EBMT centers, we examined different machine learning (ML) models to predict overall survival (OS) after transplant. The cohort was divided into a training set (75%) and a test set (25%) for model validation. A Random Survival Forests (RSF) model was developed based on 10 variables: patient age, comorbidity index, performance status, blood blasts, hemoglobin, leukocytes, platelets, donor type, conditioning intensity, and graft-versus-host disease prophylaxis. Its performance was compared with a four-level Cox regression-based score and other ML-based models derived from the same dataset, and with the CIBMTR score. The RSF outperformed all comparators, achieving better concordance indices across both primary and post-essential thrombocythemia/polycythemia vera MF subgroups. The robustness and generalizability of the RSF model was confirmed by Akaike's Information Criterion and time-dependent Receiver Operating Characteristic (ROC) Area Under the Curve (AUC) metrics in both sets. While all models were prognostic for non-relapse mortality, the RSF provided better curve separation, effectively identifying a high-risk group comprising 25% of patients. In conclusion, ML enhances risk stratification in MF patients undergoing allo-HCT, paving the way for personalized medicine. A web application (https://gemfin.click/ebmt) based on the RSF model offers a practical tool to identify patients at high risk for poor transplantation outcomes, supporting informed treatment decisions and advancing individualized care.

DOI: https://doi.org/10.1182/blood.2024027287
Blood. 2025 Mar 25. pii: blood.2024025776. [Epub ahead of print]

Tracking clusterin expression in hematopoietic stem cells reveals their heterogeneous composition across the lifespan.

Shuhei Koide, Motohiko Oshima, Takahiro Kamiya, Zhiqian Zheng, Zhaoyi Liu, Ola Rizq, Akira Nishiyama, Koichi Murakami, Yuta Yamada, Yaeko Nakajima-Takagi, Bahityar Rahmutulla, Atsushi Kaneda, Kazuaki Yokoyama, Nozomi Yusa, Seiya Imoto, Fumihito Miura, Takashi Ito, Tomohiko Tamura, Claus Nerlov, Masayuki Yamashita, Atsushi Iwama.

Hematopoietic stem cells (HSCs) exhibit significant age-related phenotypic and functional alterations. Although single-cell technologies have elucidated age-related compositional changes, prospective identification of aging-associated HSC subsets has remained challenging. In this study, utilizing Clusterin (Clu)-GFP reporter mice, we demonstrated that Clu expression faithfully marks age-associated myeloid/platelet-biased HSCs throughout life. Clu-GFP expression clearly segregates a novel age-associated HSC subset that overlaps with but is distinct from those previously identified using antibodies against aging maker proteins or reporter systems of aged HSC signature genes. Clu-positive (Clu+) HSCs emerge as a minor population in the fetus and progressively expand with age. Clu+ HSCs display not only an increased propensity for myeloid/platelet-biased differentiation but also a unique behaviour in the BM, favouring self-renewal over differentiation into downstream progenitors. In contrast, Clu-negative (Clu-) HSCs exhibit lineage-balanced differentiation, which predominates in the HSC pool during development but becomes underrepresented as aging progresses. Both subsets maintain long-term self-renewal capabilities even in aged mice but contribute differently to hematopoiesis. The predominant expansion of Clu+ HSCs largely drives the age-related changes observed in the HSC pool. Conversely, Clu- HSCs preserve youthful functionality and molecular characteristics into old age. Consequently, progressive changes in the balance between Clu+ and Clu- HSC subsets account for HSC aging. Our findings establish Clu as a novel marker for identifying aging-associated changes in HSCs and provide a new approach that enables lifelong tracking of the HSC aging process.

DOI: https://doi.org/10.1182/blood.2024025776
Ann Hematol. 2025 Mar 28.

A phase 1 study of durvalumab as monotherapy or combined with tremelimumab with or without azacitidine in patients with myelodysplastic syndrome.

Guillermo Garcia-Manero, Manila Gaddh, Uwe Platzbecker, R Coleman Lindsley, Sarah M Larson, Timothy Chevassut, Pierre Fenaux, Rami Komrokji, Roger Lyons, Aref Al-Kali, Yu Jiang, John Bothos, Danielle M Townsley, Amer M Zeidan.

  Upregulation of programmed death ligand-1 (PD-L1) has been observed in patients with MDS, and its expression on myeloblasts is associated with progression to AML. This open-label, phase 1 study evaluated the safety and tolerability of the PD-L1 antibody durvalumab as monotherapy (part 1) and in combination with tremelimumab, with or without azacitidine (part 2), in patients with MDS who progressed following hypomethylating agent treatment. Sixty-seven adults with MDS were enrolled (part 1, 40 with low/intermediate-1 or intermediate-2/high IPSS risk status; part 2, 27 with intermediate-2/high IPSS risk status). Primary safety endpoints included dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs). Secondary endpoints included evaluation of clinical outcomes, survival, and pharmacokinetics. Dose-limiting toxicities were experienced by no patients in part 1 and 3 patients (11%) in part 2. The most common treatment-emergent adverse events were diarrhea and fatigue (40% each) in part 1 and fatigue (44%) and anemia (37%) in part 2. In parts 1 and 2, 15% of patients experienced marrow complete response as their best overall response, according to IWG criteria. Hematologic improvement was observed in 35% and 30% of patients respectively in part 1 and part 2. The study was terminated early due to limited efficacy.

Keywords:  Acute myeloid leukemia; CTLA-4; Durvalumab; First-in-human; MDS; PD-L1

DOI:  https://doi.org/10.1007/s00277-024-06081-4
Clin Lymphoma Myeloma Leuk. 2025 Mar 04. pii: S2152-2650(25)00077-1. [Epub ahead of print]

Disease Phenotype Significantly Influences the Outcome After Discontinuation of Ruxolitinib in Chronic Phase Myelofibrosis.

Francesca Palandri, Massimo Breccia, Erika Morsia, Elena M Elli, Giulia Benevolo, Mario Tiribelli, Eloise Beggiato, Mirko Farina, Giovanni Caocci, Novella Pugliese, Alessia Tieghi, Monica Crugnola, Gianni Binotto, Francesco Cavazzini, Elisabetta Abruzzese, Alessandro Isidori, Alessandra Dedola, Alessandra Iurlo, Roberto M Lemoli, Daniela Cilloni, Monica Bocchia, Florian H Heidel, Massimiliano Bonifacio, Giuseppe A Palumbo, Filippo Branzanti.

   INTRODUCTION: In patients with myelofibrosis (MF), overall survival (OS) after ruxolitinib discontinuation is poor, with leukemic transformation, clonal evolution and thrombocytopenia as the main factors worsening prognosis.
PATIENTS AND METHODS: To assess the impact of disease phenotype on outcome after ruxolitinib discontinuation in chronic phase patients, we performed a sub-analysis of the "RUX-MF" study (NCT06516406), which now includes 1055 MF patients who received ruxolitinib in a real-life context.
RESULTS: After a median follow-up of 3.3 years, 397 patients discontinued ruxolitinib therapy while in chronic phase. At treatment end, 208 patients (52.4%) had a severely cytopenic phenotype (defined as platelets < 100 × 109/L and/or hemoglobin < 8 g/dL); among the remaining myeloproliferative 189 patients, 97 had no cytopenia (51.3%) and 92 (48.7%) had mild anemia only (hemoglobin between 8 and 10 g/dL). Overall, 175 patients (44.1%) had a large splenomegaly (palpable at ≥ 10 cm below costal margin). After ruxolitinib discontinuation, 3-year OS was 33.4% in severely cytopenic and 54.4% in myeloproliferative patients (P < .001); this was confirmed after adjustment for risk categories. Noncytopenic and mildly anemic patients had comparable OS (P = .73). Patients with large splenomegaly had significantly poorer OS compared to nonsplenomegalic patients (OS: 33.5% vs. 51.6% P = .01). Large splenomegaly confirmed its negative prognostic impact on OS of patients with myeloproliferative MF (60.7% vs. 44.5%, P = .05). In patients with severe cytopenia, the presence of a large splenomegaly did not influence OS (41.7% vs. 26.1%, P = .26).
CONCLUSIONS: Cytopenic phenotype and large splenomegaly in myeloproliferative MF are key prognostic determinants of outcome after ruxolitinib discontinuation.

Keywords:  Cytopenia; Cytoreductive therapy; Myeloproliferative neoplasms; Overall survival; Splenomegaly

DOI:  https://doi.org/10.1016/j.clml.2025.02.015
Biomedicines. 2025 Mar 03. pii: 619. [Epub ahead of print]13(3):

Functional Role of Fatty Acid Synthase for Signal Transduction in Core-Binding Factor Acute Myeloid Leukemia with an Activating c-Kit Mutation.

Ruimeng Zhuang, Bente Siebels, Konstantin Hoffer, Anna Worthmann, Stefan Horn, Nikolas Christian Cornelius von Bubnoff, Cyrus Khandanpour, Niklas Gebauer, Sivahari Prasad Gorantla, Hanna Voss, Hartmut Schlüter, Malte Kriegs, Walter Fiedler, Carsten Bokemeyer, Manfred Jücker, Maxim Kebenko.

  Background/Objectives: Acute myeloid leukemia (AML) is a rare hematological malignancy with a poor prognosis. Activating c-Kit (CD117) mutations occur in 5% of de novo AML and 30% of core-binding factor (CBF) AML, leading to worse clinical outcomes. Posttranslational modifications, particularly with myristic and palmitic acid, are crucial for various cellular processes, including membrane organization, signal transduction, and apoptosis regulation. However, most research has focused on solid tumors, with limited understanding of these mechanisms in AML. Fatty acid synthase (FASN), a key palmitoyl-acyltransferase, regulates the subcellular localization, trafficking, and degradation of target proteins, such as H-Ras, N-Ras, and FLT3-ITDmut receptors in AML. Methods: In this study, we investigated the role of FASN in two c-Kit-N822K-mutated AML cell lines using FASN knockdown via shRNA and the FASN inhibitor TVB-3166. Functional implications, including cell proliferation, were assessed through Western blotting, mass spectrometry, and PamGene. Results: FASN inhibition led to an increased phosphorylation of c-Kit (p-c-Kit), Lyn kinase (pLyn), MAP kinase (pMAPK), and S6 kinase (pS6). Furthermore, we observed sustained high expression of Gli1 in Kasumi1 cells following FASN inhibition, which is well known to be mediated by the upregulation of pS6. Conclusions: The combination of TVB-3166 and the Gli inhibitor GANT61 resulted in a significant reduction in the survival of Kasumi1 cells.

Keywords:  AML; Akt; Gli1; Lyn; PI3K; S6 kinase; TVB-3166; c-Kit mutation; fatty acid synthase; hedgehog signaling; mTOR; palmitoylation

DOI:  https://doi.org/10.3390/biomedicines13030619
Blood. 2025 Mar 27. 145(13): 1438

Atypical chronic myeloid leukemia: from cytology to molecular characterization.

Aida Calo-Pérez, Raquel Martínez-Fernández.

DOI: https://doi.org/10.1182/blood.2024027505
Blood Cancer J. 2025 Mar 21. 15(1): 42

Allo-HCT refined ELN 2022 risk classification: validation of the Adverse-Plus risk group in AML patients undergoing allogeneic hematopoietic cell transplantation within the Spanish Group for Hematopoietic Cell Transplantation (GETH-TC).

Carlos Jiménez-Vicente, Jordi Esteve, Mónica Baile-González, Estefanía Pérez-López, Carmen Martin Calvo, Clara Aparicio, Itziar Oiartzabal Ormategi, Albert Esquirol, Felipe Peña-Muñoz, Sara Fernández-Luis, Inmaculada Heras Fernando, Ana Pilar González-Rodríguez, Alberto López-García, Jose Luis López-Lorenzo, Tamara Torrado, Adolfo Jesús Sáez Marín, Cynthia Acosta Fleytas, Lucía García, Sara Villar, Silvia Filaferro, Pascual Balsalobre, María Jesús Pascual Cascón, María Queralt Salas.

This multicenter retrospective study by GETH-TC validates the prognostic value of the Allo-HCT Refined ELN 2022 risk classification in allografted AML patients. The new classification refines the ELN 2022 risk classification, dividing adverse-risk patients into two subgroups: Adv-Plus (AdvP), including those with complex karyotype, MECOM (EVI1) rearrangement, or TP53 mutations/del(17p), and an additional adverse group (Adv*). The study included 651 AML patients treated with at least one line of anthracycline-based induction therapy and in complete remission. According to the Allo-HCT Refined ELN 2022 risk classification, 19.4% (n = 126) patients were classified into the Favorable (Fav) risk, 38.1% (n = 248) into the Intermediate (Int) risk, 27.2% (n = 177) in the Adv* and 15.4% (n = 100) in the AdvP. Outcomes were significantly poorer for patients allocated in the AdvP risk group (5-year OS rate: 32.3%, 5-year LFS rate: 24.3%, both p < 0.001 with the rest of subgroups) and a higher CIR (5-year CIR: 64.3%, p < 0.001). Patients in the Adv* risk group had similar outcomes than patients in the Int risk group (5-year OS rate: 70.2% vs. 66.7%, p = 0.69, 5-year LFS rate: 63.8% vs. 55.9%, p = 0.33). Multivariate analysis confirmed the dismal outcomes for AdvP patients for OS: Hazard Ratio (HR) = 3.05, and LFS: HR = 2.66, both p < 0.001. Our findings validate the Allo-HCT Refined ELN 2022 classification as a robust prognostic tool, particularly highlighting the poor outcomes for the AdvP subgroup.

DOI: https://doi.org/10.1038/s41408-025-01223-x
Hemasphere. 2025 Mar;9(3): e70103

Low-risk MDS-A spotlight on precision medicine for SF3B1-mutated patients.

Shoshana Burke, Onima Chowdhury, Kevin Rouault-Pierre.

A deep understanding of the biological mechanisms driving the pathogenesis of myelodysplastic neoplasms (MDS) is essential to develop comprehensive therapeutic approaches that will benefit patient's disease management and quality of life. In this review, we focus on MDS harboring mutations in the splicing factor SF3B1. Clones harboring this mutation arise from the most primitive hematopoietic compartment and expand throughout the entire myeloid lineage, exerting distinct effects at various stages of differentiation. Supportive care, particularly managing anemia, remains essential in SF3B1-mutated MDS. While SF3B1 mutations are frequently linked with ring sideroblasts and iron overload due to impaired erythropoiesis, the current therapeutic landscape fails to adequately address the underlying disease biology, particularly in transfusion-dependent patients, where further iron overload contributes to increased morbidity and mortality. Novel agents such as Luspatercept and Imetelstat have shown promise, but their availability remains restricted and their long-term efficacy is to be investigated. Spliceosome modulators have failed to deliver and inhibitors of inflammatory pathways, including TLR and NF-κB inhibitors, are still under investigation. This scarcity of effective and disease-modifying therapies highlights the unmet need for new approaches tailored to the molecular and genetic abnormalities in SF3B1-mutated MDS. Emerging strategies targeting metabolic mis-splicing (e.g., COASY) with vitamin B5, pyruvate kinase activators, and inhibitors of oncogenic pathways like MYC and BCL-2 represent potential future avenues for treatment, but their clinical utility remains to be fully explored. The current limitations in treatment underscore the urgency of developing novel, more effective therapies for patients with SF3B1-mutated MDS.

DOI: https://doi.org/10.1002/hem3.70103
EJHaem. 2025 Apr;6(2): e70007

Real World Management of Cytopenias and Infections in Patients With Myelofibrosis Treated With Ruxolitinib.

Liesl A Butler, Cecily Forsyth, Claire Harrison, Andrew C Perkins.

Introduction: Ruxolitinib was the first JAK2 inhibitor approved for the treatment of primary and secondary myelofibrosis. It is currently used worldwide as first-line therapy for advanced disease (intermediate-2 and high-risk) and is effective in polycythaemia vera (PV) and essential thrombocythaemia (ET), but not funded for this indication in many countries. Ruxolitinib has proven benefits with respect to symptom control, reduction in spleen size and prolongation of survival; however, it rarely induces a substantial reduction in allele burden and never provides a cure. Moreover, there are frequently encountered adverse effects and dosing issues that require careful management to optimise its therapeutic benefit.
Methods and Results: In this case-based review, we use seven informative common clinical scenarios to discuss appropriate investigation and management of cytopenias and infection issues.
Conclusions: We make recommendations based on 15 years of experience in using ruxolitinib and other JAK inhibitors for the treatment of myelofibrosis. We discuss when allogeneic haematopoietic stem cell transplantation (AHSCT) should be considered and some of the currently available alternative JAK inhibitors and trial options when AHSCT is not an option.

DOI: https://doi.org/10.1002/jha2.70007
Blood Adv. 2025 Apr 08. 9(7): 1585-1586

Germ line JAK2 variants and hereditary blood cancers.

Joseph Cannova, Michael W Drazer.

DOI: https://doi.org/10.1182/bloodadvances.2025015810
Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2423776122

Cancer-associated SF3B1 mutation K700E causes widespread changes in U2/branchpoint recognition without altering splicing.

Andrey Damianov, Chia-Ho Lin, Jian Zhang, James L Manley, Douglas L Black.

  Myelodysplastic syndromes and other cancers are often associated with mutations in the U2 snRNP protein SF3B1. Common SF3B1 mutations, including K700E, disrupt SF3B1 interaction with the protein SUGP1 and induce aberrant activation of alternative 3' splice sites (ss), presumably resulting from aberrant U2/branch site (BS) recognition by the mutant spliceosome. Here, we apply a method of U2 IP-seq to profile BS binding across the transcriptome of K562 leukemia cells carrying the SF3B1 K700E mutation. For alternative 3' ss activated by K700E, we identify their associated BSs and show that they are indeed shifted from the WT sites. Unexpectedly, we also identify thousands of additional changes in BS binding in the mutant cells that do not alter splicing. These new BSs are usually very close to the natural sites, occur upstream or downstream, and either exhibit stronger base-pairing potential with U2 snRNA or are adjacent to stronger polypyrimidine tracts than the WT sites. The widespread imprecision in BS recognition induced by K700E with limited changes in 3' ss selection expands the physiological consequences of this oncogenic mutation.

Keywords:  U2 snRNP; intron branchpoint; myelodysplastic syndrome; pre-mRNA splicing

DOI:  https://doi.org/10.1073/pnas.2423776122
Hemasphere. 2025 Mar;9(3): e70104

Two distinct fetal-type signatures characterize juvenile myelomonocytic leukemia.

Marion Strullu, Chloé Arfeuille, Aurélie Caye-Eude, Loïc Maillard, Elodie Lainey, Florian Piques, Bruno Cassinat, Fabien Guimiot, Jean-Hugues Dalle, André Baruchel, Christine Chomienne, Dominique Bonnet, Michèle Souyri, Hélène Cavé.

Juvenile myelomonocytic leukemia (JMML) is an aggressive clonal myeloproliferative neoplasm that affects infants and young children. The narrow window of onset suggests that age-related factors are involved in leukemogenesis. To investigate whether ontogeny-related features are involved in JMML oncogenesis, we compared the gene expression profile of hematopoietic progenitor cells isolated from JMML patients with that of healthy individuals at different stages of ontogeny. This analysis identified two main groups of JMML patients. In the first group, JMML progenitors exhibited a gene expression profile similar to that of embryo-fetal progenitors. Progenitors showed a strong monocytic identity as evidenced by the overexpression of monocytic/dendritic, inflammasome, and innate immune markers. This resembled the monocyte-predominant myelopoiesis characteristic of normal fetal hematopoiesis. However, in the second group, despite evidence of developmental dysregulation as indicated by the aberrant signature of the master oncofetal regulator LIN28B, JMML clustered separately from healthy prenatal and postnatal fractions. These findings highlight the intricate relationship between JMML and development, which will help inform future therapeutic approaches for this rare but severe form of leukemia.

DOI: https://doi.org/10.1002/hem3.70104
Nat Commun. 2025 Mar 23. 16(1): 2846

Bemcentinib as monotherapy and in combination with low-dose cytarabine in acute myeloid leukemia patients unfit for intensive chemotherapy: a phase 1b/2a trial.

Sonja Loges, Michael Heuser, Jörg Chromik, Grerk Sutamtewagul, Silke Kapp-Schwoerer, Monica Crugnola, Nicola Di Renzo, Roberto Lemoli, Daniele Mattei, Walter Fiedler, Yesid Alvarado-Valero, Isabel Ben-Batalla, Jonas Waizenegger, Lisa-Marie Rieckmann, Melanie Janning, Maike Collienne, Charles D Imbusch, Niklas Beumer, David Micklem, Linn H Nilsson, Noëlly Madeleine, Nigel McCracken, Cristina Oliva, Claudia Gorcea-Carson, Bjørn T Gjertsen.

Beyond first line, the prognosis of relapsed/refractory (R/R) acute myeloid leukemia (AML) patients is poor with limited treatment options. Bemcentinib is an orally bioavailable, potent, highly selective inhibitor of AXL, a receptor tyrosine kinase associated with poor prognosis, chemotherapy resistance and decreased antitumor immune response. We report bemcentinib monotherapy and bemcentinib+low-dose cytarabine combination therapy arms from the completed BerGenBio-funded open-label Phase 1/2b trial NCT02488408 ( www.clinicaltrials.gov ), in patients unsuitable for intensive chemotherapy. The primary objective in the monotherapy arm was identification of maximum tolerated dose with secondary objectives to identify dose-limiting toxicities, safety and efficacy, and bemcentinib pharmacokinetic profile. In the combination arm, the primary objective was safety and tolerability, with efficacy and pharmacokinetics as secondary objectives. Safety and tolerability were based on standard clinical laboratory safety tests and Common Terminology Criteria for Adverse Events version 4. Bemcentinib monotherapy (32 R/R, 2 treatment-naïve AML and 2 myelodysplasia patients) was well-tolerated and a loading/maintenance dose of 400/200 mg was selected for combination treatment, comprising 30 R/R and 6 treatment-naïve AML patients. The most common grade 3/4 treatment-related adverse events were cytopenia, febrile neutropenia and asymptomatic QTcF prolongation, with no grade 5 events reported. In conclusion, bemcentinib+low-dose cytarabine was safe and well tolerated.

DOI: https://doi.org/10.1038/s41467-025-58179-6
Leukemia. 2025 Mar 27.

What is radiation-induced acute myeloid leukaemia/can it be accurately identified?

Christophe Badie, Robert Peter Gale.

DOI: https://doi.org/10.1038/s41375-025-02561-2
Haematologica. 2025 Mar 27.

Cytogenetic abnormalities in polycythemia vera: phenotypic correlates and prognostic relevance in 669 informative cases.

Moazah Iftikhar, Masooma Rana, Yamna Jadoon, Maymona Abdelmagid, Kaaren Reichard, Cinthya Zepeda Mendoza, Animesh Pardanani, Ayalew Tefferi, Naseema Gangat.

The main objective of the current study was to provide a detailed account on the prognostic relevance of abnormal karyotype (AK) and associated specific cytogenetic abnormalities in polycythemia vera (PV). 669 PV patients were informative, of which 436 (65%) were evaluated within 1 year of diagnosis. Karyotype was abnormal in 67 (15%) patients, including isolated abnormalities of loss of Y chromosome (-Y; N=15; 3%), +9 (N=11; 3%), del(20q) (N=10; 2%), +8 (N=4; 1%). AK correlated with older age (p.

DOI: https://doi.org/10.3324/haematol.2025.287569
Blood Adv. 2025 Mar 25. 9(6): 1474-1475

Elderberry wine and promyelocytic leukemia.

Steven D Gore.

DOI: https://doi.org/10.1182/bloodadvances.2025015905
Oncogene. 2025 Mar 27.

SUMOylation facilitates the stability of BCR-ABL to promote chronic myeloid leukemia progression.

Lu Zhang, Xuefeng Wang, Dongmei Hu, Shijie Li, Mingshan Sun, Qian Liu, Huimin Feng, Minran Zhou, Chunyan Chen, Huan Zhou, Sai Ma.

Tyrosine kinase inhibitors (TKIs) targeting the oncoprotein BCR-ABL have improved the prognosis for patients with chronic myeloid leukemia (CML). However, TKI resistance and persistent expression of BCR-ABL are responsible for the relapse and progression of CML. Here, we describe a novel approach to induce BCR-ABL protein degradation by small ubiquitin-like modifier (SUMO) modification. The E3 SUMO ligase TRIM28, upregulated during the progression of CML, promoted SUMOylation of BCR-ABL, thereby inhibiting its binding to the autophagy receptor P62 and repressing its autophagic degradation. Accordingly, genetic and pharmacological inhibition of TRIM28 or SUMOylation suppressed progression in both the CML mouse model and patient-derived xenograft model. Furthermore, targeting SUMOylation of BCR-ABL restrained the proliferation of TKI-resistant CML cells. These results identify the mechanism by which TRIM28 maintains BCR-ABL stability to promote CML progression and suggest SUMOylation as a target for CML treatment.

DOI: https://doi.org/10.1038/s41388-025-03350-y
Nat Cancer. 2025 Mar 24.

CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant.

Shunya Ikeda, Kana Hasegawa, Yosuke Kogue, Takao Arimori, Ryuhei Kawamoto, Tansri Wibowo, Moto Yaga, Yuri Inada, Hirofumi Uehara, Miwa Matsubara, Mana Tachikawa, Makiko Suga, Shuhei Kida, Kumi Shibata, Kazuhito Tsutsumi, Kentaro Fukushima, Jiro Fujita, Tomoaki Ueda, Shinsuke Kusakabe, Akihisa Hino, Michiko Ichii, Asao Hirose, Hirohisa Nakamae, Masayuki Hino, Takafumi Nakao, Megumu Inoue, Kyoko Yoshihara, Satoshi Yoshihara, Shuji Ueda, Tetsuro Tachi, Hideki Kuroda, Koki Murakami, Noriyuki Kijima, Haruhiko Kishima, Eri Igashira, Mari Murakami, Tsuyoshi Takiuchi, Tadashi Kimura, Takashi Hiroshima, Toru Kimura, Yasushi Shintani, Chihaya Imai, Kosuke Yusa, Ryota Mori, Takayuki Ogino, Hidetoshi Eguchi, Kiyoshi Takeda, Yusuke Oji, Atsushi Kumanogoh, Junichi Takagi, Naoki Hosen.

Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRB1 can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRB1 alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT.

DOI: https://doi.org/10.1038/s43018-025-00934-1