bims-tremyl 2025-01-19 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–01–19
28 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy).
CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias.
A mutant ASXL1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia.
Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial.
RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia.
The dosage of ropeginterferon in polycythaemia vera: Balancing efficacy, safety and pharmacoeconomics across risk categories.
Precision Medicine for High-Risk Gene Fusions in Pediatric AML: a focus on KMT2A, NUP98, and GLIS2 Rearrangements.
Defining 2 Biologically and Clinically Distinct Groups in Acute Leukemia with a Mixed Phenotype.
Prognostic, biological, and structural implications of FLT3-JMD point mutations in acute myeloid leukemia: an analysis of Alliance studies.
CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia.
Increased clonal hematopoiesis in long-term survivors of pediatric hematopoietic cell transplantation.
Prolonged persistence of mutagenic DNA lesions in somatic cells.
How I Treat Higher-Risk MDS.
Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial.
Monocytes generated by interleukin-6-treated human hematopoietic stem and progenitor cells secrete calprotectin that inhibits erythropoiesis.
Loss of the Inv(16) Oncogene CBFB::MYH11 Eliminates Leukemia from the Blood and Spleen, but not the Bone Marrow.
Prognostic impact of expression of CD2, CD25, and/or CD30 in/on mast cells in systemic mastocytosis: a registry study of the European Competence Network on Mastocytosis.
Impact of myelodysplasia-related and additional gene mutations in intensively treated patients with NPM1-mutated AML.
Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication.
Diverse real-life outcomes after intensive risk-adapted therapy for 1034 AML patients from the CETLAM Group.
Venetoclax in combination with fludarabine, cytarabine, granulocyte colony stimulating factor, and idarubicin (FLAG-Ida) in patients with acute leukemia of ambiguous lineage and acute lymphoblastic leukemia.
Multi-omic analysis of chronic myelomonocytic leukemia monocytes reveals metabolic and immune dysregulation leading to altered macrophage polarization.
Hypomethylating agents for patients with VEXAS without myelodysplastic syndrome: Clinical outcome and longitudinal follow-up of vacuolization and UBA1 clonal dynamics.
Relationship between additional mutations at diagnosis and treatment response in patients with essential thrombocythemia.
Safety and efficacy of the ROCK-2-inhibitor Belumosudil in cGvHD treatment - a retrospective, German-Swiss multicenter real-world data analysis.
How I Treat Anemia in Myelofibrosis.
Common Hereditary Variants of the APOE Gene and Posttransplant Outcome in Acute Myeloid Leukemia.
Subclonal TP53 and KRAS variants combined with poor treatment response identify ultra-high-risk pediatric T-ALL patients.

Hemasphere. 2025 Jan;9(1): e70057

Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy).

Martijn P T Ernst, Jurjen Versluis, Peter J M Valk, Marc Bierings, Rienk Y J Tamminga, Louise H Hooimeijer, Konstanze Döhner, Paolo Gresele, Kiran Tawana, Saskia M C Langemeijer, Bert A Van der Reijden, Helena Podgornik, Matjaz Sever, Tor H A Tvedt, Tom Vulliamy, Jude Fitzgibbon, Inderjeet Dokal, Panagiotis Baliakas, José M Bastida, Christian Pohlkamp, Torsten Haferlach, Lise Larcher, Jean Soulier, Roger E G Schutgens, Kathleen Freson, Nicolas Duployez, Bob Löwenberg, Katrin Ericson, Jörg Cammenga, Tim Ripperger, Marc H G P Raaijmakers.

Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, RUNX1-FPD), caused by monoallelic deleterious germline RUNX1 variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical data on FPDMM-associated AML (FPDMM-AML) are limited, complicating evidence-based clinical decision-making. Here, we present retrospective genetic and clinical data of the largest cohort of FPDMM patients reported to date. We describe 159 European patients (from 94 families) of whom 134 were evaluable for the development of malignant disease. Sixty developed a hematologic malignancy (44.8%), most frequently AML (36/134, 26.9%) or MDS (18/134, 13.4%). Somatic alterations of RUNX1 by gene mutation (48%) and chromosome 21 aberrations (14.3%) were the most common somatic genetic aberrations in FPDMM-AML, followed by FLT3-ITD mutations (24.1%). Somatic RUNX1 and FLT3-ITD mutations were not detected in FPDMM-associated MDS, suggesting important contributions to leukemic transformation. Remission-induction chemotherapy resulted in complete remission in 80% of FPDMM-AML patients with a 5-year overall survival (OS) of 50.4%. Survival outcome was non-inferior compared to a large cohort of newly diagnosed adult RUNX1-mutated AML (5-year OS 36.6%, p = 0.5), with relatively infrequent concurrent adverse risk somatic aberrations (ASXL1 mutation, monosomal karyotype, monosomy 5/del 5q) in FPDMM-AML. Collectively, data support the notion that step-wise leukemic evolution in FPDMM is associated with distinct genetic events and indicate that a substantial subset of FPDMM-AML patients achieves prolonged survival with conventional AML treatment, including allogeneic stem cell transplant. These findings are anticipated to inform personalized clinical decision-making in this rare disorder.

DOI: https://doi.org/10.1002/hem3.70057
bioRxiv. 2024 Dec 30. pii: 2024.12.30.630680. [Epub ahead of print]

CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias.

Travis J Fleming, Mateusz Antoszewski, Sander Lambo, Michael C Gundry, Riccardo Piussi, Lara Wahlster, Sanjana Shah, Fiona E Reed, Kevin D Dong, Joao A Paulo, Steven P Gygi, Claudia Mimoso, Seth R Goldman, Karen Adelman, Jennifer A Perry, Yana Pikman, Kimberly Stegmaier, Maria N Barrachina, Kellie R Machlus, Volker Hovestadt, Andrea Arruda, Mark D Minden, Richard A Voit, Vijay G Sankaran.

Acute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases co-opting stem cell gene regulatory programs, yet the mechanisms through which this occurs remain poorly understood. Increased expression of the stem cell transcription factor, MECOM, underlies one key driver mechanism in largely incurable AMLs. How MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, we engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem cell-like states by directly repressing pro-differentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-bound cis-regulatory element located 42 kb downstream of the myeloid differentiation regulator CEBPA, is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo, suggesting a broadly applicable differentiation-based approach for improving therapy.

DOI: https://doi.org/10.1101/2024.12.30.630680
bioRxiv. 2025 Jan 02. pii: 2024.01.30.578015. [Epub ahead of print]

A mutant ASXL1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia.

Zhen Dong, Hugo Sepulveda, Leo J Arteaga-Vazquez, Chad Blouin, Jenna Fernandez, Moritz Binder, Wen-Chien Chou, Hwei-Fang Tien, Mrinal Patnaik, Geoffrey J Faulkner, Samuel A Myers, Anjana Rao.

ASXL1 is one of the three most frequently mutated genes in age-related clonal hematopoiesis (CH), alongside DNMT3A and TET2 . CH can progress to myeloid malignancies including chronic monomyelocytic leukemia (CMML), and is also strongly associated with inflammatory cardiovascular disease and all-cause mortality in humans. DNMT3A and TET2 regulate DNA methylation and demethylation pathways respectively, and loss-of-function mutations in these genes reduce DNA methylation in heterochromatin, allowing de-repression of silenced elements in heterochromatin. In contrast, the mechanisms that connect mutant ASXL1 and CH are not yet fully understood. CH/CMML-associated ASXL1 mutations encode C-terminally truncated proteins that enhance the deubiquitinase activity of the ASXL-BAP1 "PR-DUB" deubiquitinase complex, which removes mono-ubiquitin from H2AK119Ub. Here we show that ASXL1 mutant proteins interact with the EHMT1-EHMT2 methyltransferase complex, which generates H3K9me1 and me2, the latter a repressive modification in constitutive heterochromatin. Compared to cells from age-matched wildtype mice, we found that expanded myeloid cells from old (≥18-month-old) Asxl1tm/+ mice, a heterozygous knock-in mouse model of CH, display genome-wide decreases of H3K9me2, H3K9me3 and H2AK119Ub as well as an associated increase in expression of transposable elements (TEs) and satellite repeats. Increased TE expression was also observed in monocytes from ASXL1 -mutant CMML patients compared to monocytes from healthy controls. Our data suggest that mutant ASXL1 proteins compromise the integrity of both constitutive and facultative heterochromatin in an age-dependent manner, by reducing the levels of H3K9me2/3 and H2AK119Ub. This increase in TE expression correlated with increased expression of nearby genes, including many interferon-inducible (inflammation-associated) genes (ISGs).
Significance Statement: Age-related clonal hematopoiesis (CH) is a premalignant condition associated with inflammatory cardiovascular disease. ASXL1 mutations are very frequent in CH. We show that ASXL1 interacts with EHMT1 and EHMT2, H3K9 methyltransferases that deposit H3K9me1 and me2. Using a mouse model of mutant ASXL1 to recapitulate CH, we found that old ASXL1-mutant mice showed marked expansion of myeloid cells in bone marrow, with decreased H3K9me2/3 and increased expression of transposable elements (TEs) in heterochromatin. In humans, ASXL1-mutant CH progresses to chronic monomyelocytic leukemia (CMML); CMML patient samples showed striking upregulation of many TE families, suggesting that ASXL1 mutations compromise heterochromatin integrity, hence causing derepression of TEs. Targeting heterochromatin-associated proteins and TEs might counter the progression of CH, CMML and other myeloid malignancies.

DOI: https://doi.org/10.1101/2024.01.30.578015
J Hematol Oncol. 2025 Jan 16. 18(1): 7

Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial.

Olutasidenib Combination Therapy Study Group

   BACKGROUND: Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy.
METHODS: Adult patients with mIDH1R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety.
RESULTS: Sixty-seven patients with R/R mIDH1R132 AML received combination OLU + AZA. Median age was 66 years (range 28-82) and 54% were male. Most patients (83%) had 2 + prior regimens, including a hypomethylating agent in 40%, IDH1 inhibitor therapy in 31% (olutasidenib in 24%), and hematopoietic stem cell transplant in 10%. Cytogenetic risk was intermediate in 72%, poor in 18% and unknown in 10%. CR/CRh was achieved in 21/67 (31%; 95% CI 21-44) patients, with a median duration of 14.7 months (95% CI 4.6-not reached). CR was achieved in 18/67 (27%; 95% CI 17-39) patients, with median duration of 20.3 months (95% CI 3.7-not reached). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI 38-63) patients. Median overall survival was 12.9 months (95% CI 18.7-19.3). In a subset analysis excluding patients who had prior OLU exposure (N = 51), CR/CRh was achieved in 19/51 (37%; 95% CI 24-52) patients, CR was achieved in 16/51 (31%; 95% CI 19-46), and overall response was achieved in 30/51 (59%; 95% CI 44-72). In patients who achieved CR/CRh and were transfusion-dependent at baseline, transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively. The most common Grade 3 or 4 adverse events (> 20% patients) were decreased platelet count (37%), red blood cell count (25%), and neutrophil count (24%). Six patients (9%) experienced differentiation syndrome. Four (6%) discontinued treatment due to an adverse event.
CONCLUSIONS: Olutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R AML with diverse treatment histories. The results represent another therapeutic option for patients with mIDH1 AML who may benefit from a targeted therapy.
TRIAL REGISTRATION: NCT02719574.

Keywords:  AML; Combination therapy; Hypomethylating agent; Isocitrate dehydrogenase-1; Mutant IDH1 inhibitor; Refractory; Relapsed

DOI:  https://doi.org/10.1186/s13045-024-01657-z
Nat Commun. 2025 Jan 16. 16(1): 492

RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia.

Tim Kong, Angelo B A Laranjeira, Christopher T Letson, LaYow Yu, Shuyang Lin, Jared S Fowles, Daniel A C Fisher, Sherwin Ng, Wei Yang, Fan He, Minyoung Youn, Kailen Mark, Ana San Jose, Jingxian Liu, Alexander B Kim, Maggie J Cox, Mary C Fulbright, Aarthi Jayanthan, Gerrit Los, Stacey L Rentschler, Li Ding, Kathleen M Sakamoto, Sandra E Dunn, Grant A Challen, Stephen T Oh.

Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. Combining ATAC-Seq, CUT&Tag, RNA-seq, and CyTOF, we demonstrate that targeting of ribosomal protein S6 kinase A1 (RSK1) suppresses NFκB activation and diminishes pro-inflammatory mediators including tumor necrosis factor (TNF) associated with MPN disease severity and transformation. We further evaluate a therapeutic approach utilizing a first-in-class RSK inhibitor, PMD-026, currently in Phase 2 development for breast cancer, for use in myeloid malignancies. Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML.

DOI: https://doi.org/10.1038/s41467-024-55643-7
Br J Haematol. 2025 Jan 12.

The dosage of ropeginterferon in polycythaemia vera: Balancing efficacy, safety and pharmacoeconomics across risk categories.

Tiziano Barbui, Ayalew Tefferi, Alessandro M Vannucchi.

DOI: https://doi.org/10.1111/bjh.19996
Blood. 2025 Jan 14. pii: blood.2024026598. [Epub ahead of print]

Precision Medicine for High-Risk Gene Fusions in Pediatric AML: a focus on KMT2A, NUP98, and GLIS2 Rearrangements.

Grace Egan, Sarah K Tasian.

Robust genetic characterization of paediatric AML has demonstrated that fusion oncogenes are highly prevalent drivers of AML leukemogenesis in young children. Identification of fusion oncogenes associated with adverse outcomes has facilitated risk stratification of patients, although successful development of precision medicine approaches for most fusion-driven AML subtypes have been historically challenging. This knowledge gap has been in part due to difficulties in targeting structural alterations involving transcription factors and in identification of a therapeutic window for selective inhibition of the oncofusion without deleterious effects upon essential wild-type proteins. Herein, we discuss the current molecular landscape and functional characterisation of three of the most lethal childhood AML fusion-oncogene driven subtypes harbouring KMT2A, NUP98, or CBFA2T3::GLIS2 rearrangements. We further review early-phase clinical trial data of novel targeted inhibitors and immunotherapies that have demonstrated initial success specifically for children with these poor-prognosis genetic subtypes of AML and provide appreciable optimism to improve clinical outcomes in the future.

DOI: https://doi.org/10.1182/blood.2024026598
Blood. 2025 Jan 15. pii: blood.2024026273. [Epub ahead of print]

Defining 2 Biologically and Clinically Distinct Groups in Acute Leukemia with a Mixed Phenotype.

Pallavi Galera, Deepika Dilip, Andriy Derkach, Alexander Chan, Yanming Zhang, Sonali Persaud, Tanmay Mishra, Kyle Kramer, Mahak Kathpalia, Ying Liu, Christopher A Famulare, Qi Gao, Douglas Alexander Mata, Maria E Arcila, Mark B Geyer, Eytan M Stein, Ahmet Dogan, Mikhail Roshal, Ross L Levine, Jacob L Glass, Wenbin Xiao.

A mixed phenotype is characteristic of de novo Mixed Phenotype Acute Leukemia (MPAL) but can also be seen in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with a mixed phenotype and define Acute Myeloid Leukemia with Mixed Phenotype (AML-MP) and MPAL as two distinct groups by characterizing the clinical, genetic, and transcriptomic features. Clinically, patients with AML-MP and MPAL were both treated with either AML- or acute lymphoblastic leukemia (ALL)-directed induction regimens. AML-MP shows inferior responses (HR, 12.5; 95% CI, 2.72-57.8; p=.001), while MPAL shows better responses to ALL-directed treatment. Genetically, AML-MP harbors more frequent RUNX1 (23/52, 44%) and TP53 (12/52, 23.1%) mutations. In contrast, RUNX1 mutations are less frequent in MPAL (8/35, 23%, p=.01 vs AML-MP) and TP53 mutations as a driver are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment for stemness signatures, and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation. Furthermore, AML-MP rarely switches to a lymphoid immunophenotype after treatment, in contrast to MPAL (1/40, 2.5%, vs. 10/28, 35.7%, p=.0003). Lastly, a genomic classification framework is proposed for future studies. Together, these data support the designation of AML-MP as a diagnosis distinct from MPAL and provide novel insights into the pathogenesis and therapies of acute leukemia with a mixed phenotype.

DOI: https://doi.org/10.1182/blood.2024026273
Leukemia. 2025 Jan 13.

Prognostic, biological, and structural implications of FLT3-JMD point mutations in acute myeloid leukemia: an analysis of Alliance studies.

Nadeen Anabtawi, Deedra Nicolet, Najla Alotaibi, Daelynn R Buelow, Shelley Orwick, Thomas Gregory, Ruchika Raj, Kennedy Coleman, Jonathan E Kolitz, Bayard L Powell, William G Blum, Maria R Baer, John C Byrd, Wendy Stock, Geoffrey L Uy, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Xiaolin Cheng, Sharyn D Baker, James S Blachly.

The FLT3 gene frequently undergoes mutations in acute myeloid leukemia (AML), with internal tandem duplications (ITD) and tyrosine kinase domain (TKD) point mutations (PMs) being most common. Recently, PMs and deletions in the FLT3 juxtamembrane domain (JMD) have been identified, but their biological and clinical significance remains poorly understood. We analyzed 1660 patients with de novo AML and found FLT3-JMD mutations, mostly PMs, in 2% of the patients. Patients with FLT3-JMD mutations had a higher relapse rate and shorter disease-free survival than those with FLT3-TKD, whereas their relapse rate, disease-free and overall survival were not significantly different from those of FLT3-ITD-positive patients. In vitro experiments showed that FLT3-JMD PMs transformed hematopoietic cells and responded well to type I and II FLT3 inhibitors. Molecular dynamics simulations were used to explore the conformational changes of JMD PMs relative to wild-type FLT3. These mutations exhibited constrained domain motions with wider gate openings, potentially enhancing drug binding. Altered residue interactions and structural changes shed light on their unique functional mechanisms, with increased allosteric pathways suggesting reduced interactions with other residues. We conclude that patients with FLT3-JMD PMs represent uncommon but important subset with distinct molecular and biological features, and may benefit from FLT3 inhibitors.

DOI: https://doi.org/10.1038/s41375-024-02498-y
Nat Commun. 2025 Jan 13. 16(1): 616

CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia.

Tianhui Liu, Tanzhen Wang, Lijuan Qi, Yujie Liu, Meng Shan, Fuqiang Wang, Yanglan Fang, Sining Liu, Lijun Wen, Suning Chen, Depei Wu, Yang Xu.

Acute myeloid leukemia (AML) with retinoic acid receptor gamma (RARG) fusions, which exhibits clinical features resembling acute promyelocytic leukemia (APL), has been identified as a new subtype with poor clinical outcomes. The underlying mechanism of RARG-fusion leukemia remains poorly understood, and needs to be explored urgently to instruct developing effective therapeutic strategies. Here, using the most prevalent RARG fusion, CPSF6-RARG (CR), as a representative, we reveal that the CR fusion, enhances the expansion of myeloid progenitors, impairs their maturation and synergizes with RAS mutations to drive more aggressive myeloid malignancies. Mechanistically, CR fusion interacts with histone deacetylase 3 (HDAC3) to suppress expression of genes associated with myeloid differentiation including the myeloid transcription factor PU.1. Disrupting CR-HDAC3 interaction, restores PU.1 expression and myeloid differentiation. Furthermore, HDAC inhibitors effectively suppress CR-driven leukemia in vitro and in vivo. Hence, our data reveals the molecular bases of oncogenic CR fusion and provides a potential therapeutic approach against AML with CR fusion.

DOI: https://doi.org/10.1038/s41467-024-54860-4
Blood Cancer Discov. 2025 Jan 13.

Increased clonal hematopoiesis in long-term survivors of pediatric hematopoietic cell transplantation.

Konradin F Müskens, Nienke Wieringa, Maaike G J M van Bergen, Joëll E Bense, Brigit M Te Pas, Anne P J de Pagter, Arjan C Lankester, Marc B Bierings, Donna S Neuberg, Saskia Haitjema, Leontien C M Kremer, Gerwin A Huls, Stefan Nierkens, Joop H Jansen, Caroline A Lindemans, Aniek O de Graaf, Mirjam E Belderbos.

In pediatric hematopoietic cell transplantation (HCT) recipients, transplanted donor cells may need to function far beyond normal human lifespan. Here, we investigated the risk of clonal hematopoiesis (CH) in 144 pediatric long-term HCT survivors and 258 non-transplanted controls. CH was detected in 16% of HCT recipients and 8% of controls, at variant allele frequencies (VAFs) of 0.01-0.31. Mutations were predominantly in DNMT3A (80%) and TET2 (20%). Older hematopoietic age (odds ratio: 1.07, p<0.001) and the HCT procedure (odds ratio: 2.53, p=0.02) independently increased the risk of CH, indicating both aging- and transplantation-induced effects. Large clones (VAF >0.10) were found exclusively in HCT recipients. Notably, CH was also detected within 15 years after a cord blood HCT. Inflammatory processes around graft infusion were associated with CH presence. Future studies are required to track the evolution of post-transplant CH and its impact on future cardiovascular disease, second malignancies and overall survival.

DOI: https://doi.org/10.1158/2643-3230.BCD-24-0136
Nature. 2025 Jan 15.

Prolonged persistence of mutagenic DNA lesions in somatic cells.

Michael Spencer Chapman, Emily Mitchell, Kenichi Yoshida, Nicholas Williams, Margarete A Fabre, Anna Maria Ranzoni, Philip S Robinson, Lori D Kregar, Matthias Wilk, Steffen Boettcher, Krishnaa Mahbubani, Kourosh Saeb Parsy, Kate H C Gowers, Sam M Janes, Stanley W K Ng, Matt Hoare, Anthony R Green, George S Vassiliou, Ana Cvejic, Markus G Manz, Elisa Laurenti, Iñigo Martincorena, Michael R Stratton, Jyoti Nangalia, Tim H H Coorens, Peter J Campbell.

DNA is subject to continual damage, leaving each cell with thousands of individual DNA lesions at any given moment1-3. The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours3,4, but the extent to which DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 818 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium5-12. Persistent DNA lesions occurred at increased rates, with distinctive mutational signatures, in donors exposed to tobacco or chemotherapy, suggesting that they can arise from exogenous mutagens. In haematopoietic stem cells, persistent DNA lesions, probably from endogenous sources, generated the characteristic mutational signature SBS1913; occurred steadily throughout life, including in utero; and endured for 2.2 years on average, with 15-25% of lesions lasting at least 3 years. We estimate that on average, a haematopoietic stem cell has approximately eight such lesions at any moment in time, half of which will generate a mutation with each cell cycle. Overall, 16% of mutations in blood cells are attributable to SBS19, and similar proportions of driver mutations in blood cancers exhibit this signature. These data indicate the existence of a family of DNA lesions that arise from endogenous and exogenous mutagens, are present in low numbers per genome, persist for months to years, and can generate a substantial fraction of the mutation burden of somatic cells.

DOI: https://doi.org/10.1038/s41586-024-08423-8
Blood. 2025 Jan 14. pii: blood.2024025271. [Epub ahead of print]

How I Treat Higher-Risk MDS.

Alain Mina, Rami S Komrokji.

Myelodysplastic syndromes/neoplasms (MDS) are a widely heterogenous group of myeloid malignancies characterized by morphologic dysplasia, a defective hematopoiesis, and recurrent genetic abnormalities. The original and revised International Prognostic Scoring Systems (IPSS) have been used to risk-stratify patients with MDS to guide treatment strategies. In higher-risk MDS, the therapeutic approach is geared toward delaying leukemic transformation and prolonging survival. For over a decade, the hypomethylating agents azacitidine and decitabine have been the standard of care and, when feasible, an allogeneic hematopoietic stem cell transplantation (AHSCT) should be considered. However, the IPSS scoring systems solely rely on clinical, morphological, and cytogenetic features and do not account for somatic mutations present in over 80% of cases. These genetic abnormalities have been shown to play a crucial role in prognostication, prompting the development of molecular IPSS, and the integration of genomic features into MDS classification systems in recent years. In this review, we delineate our approach to higher-risk MDS in the context of updated classifications and the latest prognostication tools. We employ illustrative clinical cases to support our discussion and share insights from recent clinical trials, highlighting lessons learned.

DOI: https://doi.org/10.1182/blood.2024025271
BMC Cancer. 2025 Jan 10. 25(1): 56

Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial.

Graham McIlroy, Charlotte Gaskell, Aimee Jackson, Emily Yafai, Rachel Tasker, Catherine Thomas, Sonia Fox, Rebecca Boucher, Fitsum Ghebretinsea, Claire Harrison, Adam J Mead, Mary Frances McMullin.

   BACKGROUND: Myelofibrosis (MF) is a clonal haematopoietic disease, with median overall survival for patients with primary MF only 6.5 years. The most frequent gene mutation found in patients is JAK2V617F, causing constitutive activation of the kinase and activation of downstream signalling. Fedratinib is an oral selective JAK2 inhibitor. It has shown activity in MF and is well-tolerated, but combination with other therapies is likely needed to achieve clonal remission. Combining a JAK2 inhibitor with an interferon may be synergistic, as haematopoietic cells are activated from quiescence (a typical kinase resistance mechanism) rendering them more sensitive to inhibition. Ropeginterferon alfa-2b is a next generation pegylated interferon-α-2b with high tolerability and clinical activity in patients with MF, however, evidence of tolerability and activity in combination with fedratinib is lacking in this setting. The aim of the FEDORA trial is to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b in patients with MF who require treatment to justify further investigation in a phase III trial.
METHODS: FEDORA is a single arm, multicentre, open-label, Bayesian phase II trial to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b aiming to recruit 30 patients. Patients with JAK2V617F positive primary or secondary MF, who are aged ≥ 18 years, have intermediate-1 with palpable splenomegaly of > 5cm, intermediate-2, or high-risk disease according to the Dynamic International Prognostic Scoring System (DIPSS), and who require treatment are eligible. The primary outcome is tolerability, whereby the combination is deemed intolerable in a patient if drug-related toxicities in the first four months of treatment lead to: either drug being discontinued; delays in treatment exceeding 28 consecutive days; or death. FEDORA uses a within-patient dose escalation regimen to ensure each patient reaches a personalised dose combination that is acceptable.
DISCUSSION: FEDORA is using a Bayesian trial design and aims to provide evidence of the tolerability, safety, and activity of combining fedratinib with ropeginterferon alfa-2b upon which the decision as to whether a phase III trial is warranted will be based.
TRIAL REGISTRATION: EudraCT number: 2021-004056-42.
ISRCTN: 88,102,629.

Keywords:  Bayesian design; Clinical trial; Fedratinib; JAK2 inhibition; Myelofibrosis; Phase II; Ropeginterferon alfa-2b; Tolerability

DOI:  https://doi.org/10.1186/s12885-024-13383-3
iScience. 2025 Jan 17. 28(1): 111522

Monocytes generated by interleukin-6-treated human hematopoietic stem and progenitor cells secrete calprotectin that inhibits erythropoiesis.

Valentine Marchand, Lucie Laplane, Louis Valensi, Isabelle Plo, Marine Aglave, Aymeric Silvin, Florence Pasquier, Françoise Porteu, William Vainchenker, Dorothée Selimoglu-Buet, Nathalie Droin, Hana Raslova, Virginie Marcel, Jean-Jacques Diaz, Michaela Fontenay, Eric Solary.

  Elevated circulating levels of calprotectin (CAL), the S100A8/A9 heterodimer, are biomarkers of severe systemic inflammation. Here, we investigate the effects of CAL on early human hematopoiesis. CAL demonstrates limited impact on gene expression in stem and progenitor cells, in contrast with interleukin-6 (IL6), which promotes the expression of the S100A8 and S100A9 genes in hematopoietic progenitors and the generation of monocytes that release CAL. The main target of CAL is an erythroid-megakaryocyte progenitor (EMP) subset. CAL prevents both erythropoietin-driven differentiation of healthy progenitors and JAK2-V617F-driven erythropoiesis. In the context of JAK2-V617F, CAL also promotes the expression of S100A8 and S100A9 genes in monocytes. The signature of CAL effects is detected in the bone marrow progenitors of patients with myeloid malignancy or severe infection. These results position CAL as a mediator of IL6 effects on triggering anemia during inflammation, an effect that is amplified in the context of JAK2-V617F-driven hematopoiesis.

Keywords:  Cell biology; Pathology

DOI:  https://doi.org/10.1016/j.isci.2024.111522
bioRxiv. 2024 Oct 06. pii: 2024.10.06.616896. [Epub ahead of print]

Loss of the Inv(16) Oncogene CBFB::MYH11 Eliminates Leukemia from the Blood and Spleen, but not the Bone Marrow.

Sipra Panda, Yiqian Wang, Michelle Becker, Arjun Dhir, Calvin Lam, Cecilia Rivas, Lemlem Alemu, Lisa Garrett, Samantha Swenson, R Katherine Hyde.

Inversion of chromosome 16 [inv(16)] is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML) and generates the fusion gene CBFB::MYH11 (CM) , which initiates leukemogenesis. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption that CM is required after leukemic transformation. However, this has yet to be shown experimentally. Using a knock-in mouse that allows for deletion of CM after leukemia development, we found that loss of the fusion gene increased apoptosis and decreased colony growth in vitro . Interestingly, 5-20% of the colonies had successfully deleted CM . To test the role of CM in vivo , we used an inducible shRNA knockdown (KD) construct against the fusion gene. We found that decreased CM expression eliminated leukemia cells from the peripheral blood and spleen, but not the bone marrow, despite these cells showing significant knockdown of CM at the mRNA and protein levels. Furthermore, with prolonged KD of CM , ∼40% of mice re-established disease while maintaining KD of the fusion gene. Our work indicates that CM is required by leukemia cells in the spleen and blood, but that cells in the bone marrow can survive and re-establish disease independent of the fusion protein.

DOI: https://doi.org/10.1101/2024.10.06.616896
Leukemia. 2025 Jan 15.

Prognostic impact of expression of CD2, CD25, and/or CD30 in/on mast cells in systemic mastocytosis: a registry study of the European Competence Network on Mastocytosis.

Axel Rüfer, Henning Nilius, Olivier Hermine, Marek Niedoszytko, Joanne N G Oude Elberink, Patrizia Bonadonna, Khalid Shoumariyeh, Theo Gulen, Karin Hartmann, Vito Sabato, Irena Angelova-Fischer, Daniel Baffoe, Deborah Christen, Anna Belloni Fortina, Christine Breynaert, Knut Brockow, Nikolas von Bubnoff, Horia Bumbea, Paul van Daele, Michael Doubek, Ingunn Dybedal, Chiara Elena, Christos Fokoloros, Aleksandra Górska, Marc Heizmann, Madlen Jentzsch, Saskia Klein, Johannes Lübke, Mattias Mattsson, André Mulder, Jens Panse, Tanja Daniela Schug, Mariarita Sciumè, Alex Stefan, Marlena Sztormowska, Judit Várkonyi, Friederike Wortmann, Akif Selim Yavuz, Martina Sperr, Jason Gotlib, Andreas Reiter, Massimo Triggiani, Wolfgang R Sperr, Peter Valent.

Expression of CD2, CD25 and/or CD30 in extracutaneous mast cells (MC) is a minor diagnostic criterion for systemic mastocytosis (SM) in the classification of the World Health Organization and International Consensus Classification. So far, it remains unknown whether expression of these antigens on MC is of prognostic significance in SM. We performed a retrospective multi-center study of patients with SM using the data set of the registry of the European Competence Network on Mastocytosis, including 5034 patients with various MC disorders. The percentage of CD2-, CD25+ and/or CD30+ MC was considerably lower in patients with indolent SM compared to patients with advanced SM, including aggressive SM and MC leukemia. Whereas CD25 and CD30 expression in MC could not be associated with prognosis, we found that lack of CD2 expression in MC is associated with a significantly reduced overall survival (OS) in patients with SM (p < 0.0001). Lack of CD2 was also associated with the presence of extramedullary involvement affecting the spleen, liver, and/or lymph nodes (odds ratio 2.63 compared to SM with CD2+ MC). Together, lack of CD2 expression in MC is a prognostic marker and indicator of reduced OS and extramedullary disease expansion in patients with SM.

DOI: https://doi.org/10.1038/s41375-024-02504-3
Hemasphere. 2025 Jan;9(1): e70060

Impact of myelodysplasia-related and additional gene mutations in intensively treated patients with NPM1-mutated AML.

Sibylle Cocciardi, Maral Saadati, Nina Weiß, Daniela Späth, Silke Kapp-Schwoerer, Isabelle Schneider, Annika Meid, Verena I Gaidzik, Sabrina Skambraks, Walter Fiedler, Michael W M Kühn, Ulrich Germing, Karin T Mayer, Michael Lübbert, Elli Papaemmanuil, Felicitas Thol, Michael Heuser, Arnold Ganser, Lars Bullinger, Axel Benner, Hartmut Döhner, Konstanze Döhner.

This study aimed to evaluate the impact of the myelodysplasia-related gene (MRG) as well as additional gene mutations on outcomes in intensively treated patients with NPM1-mutated (NPM1 mut) AML. Targeted DNA sequencing of 263 genes was performed in 568 NPM1 mut AML patients (median age: 59 years) entered into the prospective AMLSG 09-09 treatment trial. Most commonly co-mutated genes were DNMT3A (49.8%), FLT3-TKD (25.9%), PTPN11 (24.8%), NRAS (22.7%), TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3-ITD (17.3%). MRG mutations were identified in 18.1% of cases (18-60 years: 9.8%; >60 years: 28.7%). When focusing on the 470 patients with 2022 ELN favorable-risk NPM1 mut AML, multivariable analysis for event-free survival (EFS) identified age (p < 0.001), DNMT3A R882 (p < 0.001), IDH1 (p = 0.007), and MRG mutations (p = 0.03) as unfavorable factors, cohesin gene co-mutations (p = 0.001) and treatment with gemtuzumab ozogamicin (p = 0.007) as favorable factors. Restricting the analysis to a subset of CR/CRi patients with available data on NPM1 mut measurable residual disease (MRD) status in blood post cycle 2 in the model, MRG mutations lost their significant effect, whereas DNMT3A R882, MYC, and cohesin gene mutations retained the adverse and favorable effects. For OS, age (p < 0.001), DNMT3A R882 (p = 0.042), IDH1 (p = 0.045), and KRAS (0.003) mutations were unfavorable factors, sole favorable factor was IDH2 co-mutation (p = 0.037). In 2022 ELN favorable-risk NPM1 mut AML, MRG mutations are associated with inferior EFS; however, this effect is no longer present when considering NPM1 mut MRD status post cycle 2; DNMT3A R882 and MYC mutations remained adverse, and cohesin gene mutations favorable prognostic factors independent of the NPM1 mut MRD status.

DOI: https://doi.org/10.1002/hem3.70060
Nat Commun. 2025 Jan 10. 16(1): 560

Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication.

Dohoon Lee, Bonil Koo, Seokhyeon Kim, Jamin Byun, Junshik Hong, Dong-Yeop Shin, Choong-Hyun Sun, Jaesung Kim, Ji-Joon Song, Siddhartha Jaiswal, Sung-Soo Yoon, Sun Kim, Youngil Koh.

The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. Motivated by a recent discovery of the significance of DNMT3A-destabilizing mutations (DNMT3AINS) in AML, we here investigate the common characteristics of DNMT3AINS AML methylomes through computational analyses. We present that methylomes of DNMT3AINS AMLs are considerably different from those of DNMT3AR882 AMLs in that they exhibit increased intratumor DNA methylation heterogeneity in bivalent chromatin domains. This epigenetic heterogeneity was associated with the transcriptional variability of developmental and membrane-associated factors shaping stem cell niche, and also was a predictor of the response of AML cells to hypomethylating agents, implying that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Altogether, our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions.

DOI: https://doi.org/10.1038/s41467-024-55691-z
Blood Cancer J. 2025 Jan 11. 15(1): 4

Diverse real-life outcomes after intensive risk-adapted therapy for 1034 AML patients from the CETLAM Group.

Guadalupe Oñate, Ana Garrido, Montserrat Arnan, Helena Pomares, Ester Alonso, Mar Tormo, Marina Diaz-Beya, Susana Vives, Lurdes Zamora, Antonia Sampol, Rosa Coll, Olga Salamero, Marta Cervera, Antoni Garcia, Ferran Vall-Llovera, Sara Garcia-Avila, Joan Bargay, Xavier Ortin, Eva Iranzo, Francisca Guijarro, Marta Pratcorona, Josep F Nomdedeu, Jordi Esteve, Jorge Sierra.

Given the heterogeneity of acute myeloid leukemia patients, it is necessary to identify patients considered fit for intensive therapy but who will perform poorly, and in whom alternative approaches deserve investigation. We analyzed 1034 fit adults ≤70 years intensively treated between 2012 and 2022 in the CETLAM group. Young adults ( ≤ 60 years) presented higher remission rates and improved survival than older adults above that age (CR 79% vs. 73%; p = 0.03 and 4-yr OS 53% vs. 33%; p < 0.001). Remission and survival outcomes varied among different genetic subsets. An especially adverse genetic group included complex, monosomal karyotype, TP53 alterations (deleted/mutated), and MECOMr. Transplant feasibility in this very adverse risk group was low, and OS and EFS at 4 years were 14% and 12%, in contrast to 70% and 57% in the favorable group and 38% and 32% in all other patients. We integrated clinical and genetic data into the Intensive Chemotherapy Score for AML (ICSA) with 6-risk categories with significantly different remission rates and OS, validated in another cohort of 581 AML patients from a previous CETLAM protocol. In summary, we identified groups of fit patients that benefit differently from an intensive approach which may be helpful in future treatment decisions.

DOI: https://doi.org/10.1038/s41408-024-01205-5
Leuk Lymphoma. 2025 Jan 16. 1-5

Venetoclax in combination with fludarabine, cytarabine, granulocyte colony stimulating factor, and idarubicin (FLAG-Ida) in patients with acute leukemia of ambiguous lineage and acute lymphoblastic leukemia.

Steven Tessier, Kristen B McCullough, Naseema Gangat, Kebede H Begna, Antoine N Saliba, Abhishek A Mangoankar, Mithun V Shah, William J Hogan, Mrinal M Patnaik, Aref Al-Kali, Hassan B Alkhateeb.



Keywords:  ALL; FLAG-Ida; ambiguous lineage; relapsed/refractory; venetoclax

DOI:  https://doi.org/10.1080/10428194.2024.2443017
Leukemia. 2025 Jan 15.

Multi-omic analysis of chronic myelomonocytic leukemia monocytes reveals metabolic and immune dysregulation leading to altered macrophage polarization.

Hasse M Addinsell, Rachel Cant, Nathan J Hull, Yu-Hung Wang, Tim C P Somervaille, Daniel H Wiseman, Kiran Batta.

DOI: https://doi.org/10.1038/s41375-024-02511-4
Br J Haematol. 2025 Jan 13.

Hypomethylating agents for patients with VEXAS without myelodysplastic syndrome: Clinical outcome and longitudinal follow-up of vacuolization and UBA1 clonal dynamics.

Jose R Álamo, Lucía Mont-de Torres, Sandra Castaño-Díez, Anna Mensa-Vilaró, M Mónica López-Guerra, Ines Zugasti, Johana Díaz, Carlos Jiménez-Vicente, Susana Plaza, Virginia Fabregat, Iñaki Ortiz de Landazuri, Jordi Yagüe, Gerard Espinosa, Raimon Sanmartí, Maria Rozman, Francesca Guijarro, Albert Cortes, Ana Triguero, Aina Cardús, Adriana Cuartas, Marina Cornejo, Jordi Esteve, Juan I Aróstegui, Marina Díaz-Beyá.

  VEXAS syndrome is a haemato-inflammatory disease caused by somatic UBA1 mutations and characterized by cytoplasmic vacuoles in myeloid and erythroid precursor cells. Although there is currently no standard treatment algorithm for VEXAS, patients are generally treated with anti-inflammatory therapies focused on symptom management, with only partial effectiveness. Hypomethylating agents (HMA) have shown promise in VEXAS patients with concomitant myelodysplastic syndrome (MDS), while the efficacy of HMA in VEXAS patients without MDS is largely unknown. Furthermore, the usefulness of monitoring the variant allele frequency (VAF) of UBA1 or vacuolization in precursor cells over the course of treatment has not been extensively investigated. We have evaluated the efficacy of HMA in four VEXAS patients without MDS and performed longitudinal analyses of the VAF of UBA1 and vacuolization during treatment. HMA treatment led to overall clinical improvement, a dramatic reduction in the VAF of UBA1, normalization of haematological and inflammatory markers and a quantifiable decrease in vacuolization, leading us to speculate that unlike anti-inflammatory therapies, HMA may well act as a disease-modifying treatment. If these findings are confirmed in further studies, it could lead to the early use of HMA in the treatment of all VEXAS patients-with or without MDS.

Keywords:  UBA1 mutation; VEXAS syndrome; hypomethylating agents; myelodysplastic syndrome; vacuoles

DOI:  https://doi.org/10.1111/bjh.19953
Blood Adv. 2025 Jan 16. pii: bloodadvances.2024014791. [Epub ahead of print]

Relationship between additional mutations at diagnosis and treatment response in patients with essential thrombocythemia.

Carole Mosnier, Sarah Bellal, Laurane Cottin, Francoise Boyer-Perrard, Sandrine Lemoine, Amélie Bachelot, Joris Argentin, Bertille Pawlicki, Marie-Christine Copin, Rébecca Jouanneau-Courville, Anaïs Malinge, Jérémie Riou, Mathilde Hunault, Valérie Ugo, Corentin Orvain, Damien Luque Paz.

Patients with essential thrombocythemia (ET) have a chronic evolution with a risk of hematological transformation associated with a dismal outcome. Since patients with resistance or intolerance have an adverse prognosis, it is important to identify which patient will respond to first-line treatment. We therefore aim to describe the association between additional mutations and response to first-line treatment in patients with ET. In this retrospective study, we analyzed the molecular landscape of 121 ET patients first-line treated with hydroxyurea (n=86) or pegylated interferon (n=35). Patients undergoing peg-IFN therapy were younger and had higher proportion of low and very low risk of thrombosis recurrence. Sixty-two patients (51%) had ≥1 additional mutations at diagnosis. The most frequent additional mutations involved TET2 (15.7%) DNMT3A (10.7%), non-W515-MPL (6.6%), ASXL1 (4.13%), and splicing factors SRSF2 and SF3B1 (6.6%) genes. At 12-months of treatment, 75 (62%) patients achieved complete response (CR), 37 (31%) partial response, and 7 (6%) no response. The presence of at least one additional mutation at diagnosis was associated with not achieving CR (HR: 0.66;p=0.045), whereas treatment with interferon was associated with higher CR (HR: 2.01;p=0.002). The number of additional mutations at diagnosis was associated with hematologic progressions (p<0.0001). None of the patients receiving peg-IFN therapy progressed to myelofibrosis, while 16/86 patients (19%) treated with HU developed secondary myelofibrosis. In conclusion, our results suggest that the presence of at least one additional mutation at diagnosis is associated with failure to achieve CR and is also associated with an increased risk of hematologic evolution.

DOI: https://doi.org/10.1182/bloodadvances.2024014791
Bone Marrow Transplant. 2025 Jan 14.

Safety and efficacy of the ROCK-2-inhibitor Belumosudil in cGvHD treatment - a retrospective, German-Swiss multicenter real-world data analysis.

Silke Heidenreich, Katharina Egger-Heidrich, Jörg P Halter, Lasse Jost, Friedrich Stölzel, Markus Perl, Alexander Denk, Matthias Edinger, Wolfgang Herr, Nicolaus Kröger, Daniel Wolff, Francis Ayuk, Matthias A Fante.

Belumosudil is a first in class ROCK2-inhibitor approved by the FDA for the 3rd line treatment of chronic graft-versus-host disease (cGvHD). In this retrospective real-world analysis, we report safety and efficacy data of belumosudil treatment from 5 German/Swiss transplant centers. A total of 33 adult patients (median age 59 years) with moderate (n = 2) or severe (n = 31) cGvHD were treated on individual request due to lack of EMA approval. The patient cohort had a long history of cGvHD (median 44 months) and was heavily pretreated (median 4 prior lines). The overall response rate was 42% (95%CI, 25-60%) including organ responses in all organs except the liver (n = 2). The median time to response was 3 months (range, 1-9 months) and 8 of 14 patients (57%) had a durable response at last follow-up. One-third of patients had at least a 50% reduction in concomitant corticosteroid dosage. Median failure-free survival and median overall survival were 16.5 and 23.1 months, respectively. Adverse events ≥CTCAE grade 3 were reported in 27% of patients, with a predominance of infectious events, including one fatal course. The results are consistent with previous prospective trials including a favorable safety profile, while acknowledging the challenges of a heavily pretreated patient cohort.

DOI: https://doi.org/10.1038/s41409-024-02507-9
Blood. 2025 Jan 14. pii: blood.2023022414. [Epub ahead of print]

How I Treat Anemia in Myelofibrosis.

Akriti G Jain, Aaron T Gerds.

Anemia is a common consequence of myelofibrosis. The treatment of myelofibrosis-associated anemia is complicated by a multifactorial pathobiology, as well as a lack of therapies that result in normalization of the bone marrow and complete restoration of its function. Established agents that are used to treat anemia in other bone marrow failure states such as myelodysplastic syndromes and aplastic anemia, are used for the treatment of myelofibrosis-associated anemia. However, there has been rapid development of new anemia-directed therapies; some of which have garnered regulatory approval. In addition to adopting therapies from other disease states, better understating of the root causes of myelofibrosis-associated anemia has positioned the field to be on the cutting edge of new anemia treatments, spearheading the advancement of agents that work on the hepcidin pathway to improve red cell production.

DOI: https://doi.org/10.1182/blood.2023022414
Blood. 2025 Jan 15. pii: blood.2024026886. [Epub ahead of print]

Common Hereditary Variants of the APOE Gene and Posttransplant Outcome in Acute Myeloid Leukemia.

Julian Ronnacker, Michael Grau, Maximilian Klasmeier, Christian Klesse, Henning Baldauf, Stefan Abert, Andrew F Berdel, Friederike T Füsser, Sarah Sandmann, Jorn C Albring, Christian Reicherts, Simon Call, Julia Marx, Matthias Floeth, Eva Esseling, Lina Kolloch, Philipp Berning, Annika Scheller, Klaus Wethmar, Hartmut Schmidt, Bernhard Schlüter, Wolfgang E Berdel, Benjamin N Ostendorf, Sohail F Tavazoie, Jan-Henrik Mikesch, Georg Lenz, Katharina Fleischhauer, Johannes Schetelig, Matthias Stelljes, Christoph Schliemann.

Apolipoprotein E (APOE) has multiple functions in metabolism and immunoregulation. Its common germline variants APOE2, APOE3 and APOE4 give rise to three functionally distinct gene products. Previous studies reported yin-yang roles of APOE2 and APOE4 in immunological processes, but their effects in hematopoietic stem cell transplantation (HSCT) have never been studied. We performed APOE genotyping in two contemporary cohorts of 348 and 447 patients with acute myeloid leukemia (AML) who had received allogeneic HSCT and evaluated associations of recipient and donor APOE genetic variation with posttransplant outcome. Patients who carried at least one APOE2 allele had a higher risk of posttransplant death compared to APOE4 carriers in the discovery (hazard ratio [HR] 2.09, P = .024) and validation cohorts (HR 1.96, P = .040). Detrimental APOE2 effects were driven by an increased risk of severe chronic graft-versus-host disease (GvHD; HRadj 1.85, P = .034) and non-relapse death (HRadj 1.72, P = .044). In non-APOE2 recipients, transplantation of an APOE2-positive allograft was associated with an increased incidence of grade III-IV acute GvHD (HRadj 2.82, P = .012) and severe chronic GvHD (HRadj 2.54, P = .022) compared to APOE2-negative grafts. In summary, the APOE2 allele, typically considered a longevity gene in the general population, was associated with a higher risk of acute GvHD (HRadj 2.75, P = .002), chronic GvHD (HRadj 2.57, P = .001), and posttransplant mortality (HRadj 1.79, P = .004), when present either in the host or transplanted from the donor.

DOI: https://doi.org/10.1182/blood.2024026886
Blood Adv. 2025 Jan 14. pii: bloodadvances.2024014209. [Epub ahead of print]

Subclonal TP53 and KRAS variants combined with poor treatment response identify ultra-high-risk pediatric T-ALL patients.

Tamara Kempter, Paulina Richter-Pechanska, Katarzyna Michel, Tobias Rausch, Büşra Erarslan Uysal, Cornelia Eckert, Martin Zimmermann, Martin Stanulla, Martin Schrappe, Gunnar Cario, Stefan Köhrer, Andishe Attarbaschi, Jan O Korbel, Joachim B Kunz, Andreas Kulozik.

Variations in the TP53 and KRAS genes indicate a particularly adverse prognosis in relapsed pediatric T-ALL. We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined two cohorts of children diagnosed with T-ALL: one with 81 patients who relapsed and 79 matched non-relapsing controls, and another with 226 consecutive patients, 30 of whom relapsed. In cohort 1, targeted sequencing revealed TP53 clonal and subclonal variants in 6 of 81 relapsing patients but none in the non-relapsing group (p=0.014). KRAS alterations were found in 9 of 81 relapsing patients compared to 2 of 79 non-relapsing patients (p=0.032). Survival analysis showed that none of the relapsed patients with TP53 and/or KRAS alterations survived, whereas 19 of 67 relapsed patients without such variants did with a minimum follow-up time of 3 years (p=0.023). In cohort 2, none of the relapsing patients but 10 of 196 non-relapsing patients carried TP53 or KRAS variants, indicating that mutation status alone does not predict poor prognosis. All ten non-relapsing patients with mutations had a favorable early treatment response. Among the total cohort of 386 patients, 188 showed poor treatment response of whom 69 relapsed. Nine of these poor responders harbored TP53 or KRAS variants. In conclusion, subclonal TP53 and KRAS alterations identified at the time of initial diagnosis, along with a poor treatment response, characterize a subset of children with T-ALL who face a dismal prognosis and may benefit from alternative treatment approaches.

DOI: https://doi.org/10.1182/bloodadvances.2024014209