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European Journal of Haematology

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Online ISSN: 1600-0609

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Print ISSN: 0902-4441

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AEML in young adults (18–60 years). (A) Classification of the AEML patients according to ICC 2022 and WHO criteria (n = 41 patients for whom data were available) The categories of AML in the ICC and WHO classifications are colored grey. MDS or MDS/AML categories (for ICC) are in white. (B) Molecular landscape (performed for n = 43 patients). RAS pathway: NRAS, KRAS, PTPN11, RIT1, CBL; Cohesin: RAD21, SMC1A, SMC3, STAG2; Spliceosome: SF3B1, SRSF2, U2AF1, ZRSR2. (C) Disease‐free survival and (D) overall survival according to the blast infiltration above (AML) or below (oligo‐AML) 20% among total BM nucleated cells (n = 41 patients receiving intensive chemotherapy for whom data were available).
AEML with NPM1 mutations in young adults. (A) May‐Grünwald‐Giemsa‐stained bone marrow smear in a 40‐year‐old female patient with NPM1 mutation (VAF 46%). The complete blood count showed pancytopenia (WBC 4.6 × 10⁹/L, hemoglobin 7.3 g/dL, platelets 89 × 10⁹/L). The bone marrow (performed twice with reproducible results) showed 6% myeloid blasts with erythroid hyperplasia (72% erythroblasts) and dysmyelopoiesis. (B) Pattern of co‐mutations in NPM1‐mutated AML according to the FAB subtype. (C) Disease‐free survival and (D) overall survival in AEML/M6‐FAB AML with NPM1 mutation compared to non‐M6‐FAB AML with NPM1 mutations.
Myeloid Neoplasms With Erythroid Predominance and Excess Blasts in Young Adults Exhibit Distinct Genetic Profiles

May 2025

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The European Journal of Haematology is an international haematology journal for communication of basic and clinical research in haematology and related areas of thrombosis, haemostasis and haemophilia. We welcome manuscripts on molecular, cellular and clinical research on diseases of the blood, vascular and lymphatic tissue, and on basic molecular and cellular research related to normal development and function of the blood, vascular and lymphatic tissue. We provide a simplified submission process that works collaboratively across haematology so every submitted paper has a home.

Recent articles


Histological, electron microscopy, genetic, and proteomic analyzes in Case 1. Congo red stain of kidney tissue showing interstitial amyloid deposits viewed by light microscopy. Glomerular amyloid deposits were also present, but were not represented on this section (A). Congo red‐stained kidney tissue showing interstitial amyloid deposits (B) and glomerular and interstitial amyloid deposits (C) viewed under fluorescent light. Original magnification ×100. Electron micrographs showing haystack‐like organization of amyloid fibrils in the extracellular space of fat pad aspirate (D, E). Immunogold labeling demonstrating numerous electron dense deposits with antibody directed against immunoglobulin lambda LC (D). Negative immunogold labeling with antibody directed against immunoglobulin kappa LC (E). Original magnification, ×25 000. Negative immunogold labeling results for TTR and amyloid A are not shown. Partial sequence chromatogram of the GSN gene with p.R481C (R454C) amino acid replacement (F). The black arrow indicates a single base nucleotide transition, c.1441C>T, at the first base position of the CGC codon in exon 10. In the single nucleotide polymorphisms (SNP) database, this single nucleotide replacement is enumerated as rs116185403 (https://www.ncbi.nlm.nih.gov/snp/rs116185403). The T allele is reported in the Exome Aggregation Consortium with a frequency of 0.27% among 121 322 alleles from European, Asian, American, and African individuals, indicating a rare single nucleotide variant. Eight submissions in the ClinVar database reported this single nucleotide variant as benign or likely benign either without providing the information on associated condition or in association with inborn genetic diseases, GSN‐related disorder and Finnish type amyloidosis (accessed in September 2024). Of 6 in silico prediction algorithms used to assess the effect of GSN amino acid replacement, p.R481C (R454C) was predicted by two to have deleterious or probably damaging functional consequences. The prediction by the PolyPhen‐2 algorithm is shown (G). Scaffold readout of the top 10 proteins identified by LC–MS/MS in Congo red‐positive areas of renal biopsy (H). The number in the green box denotes the total number of detected MS/MS spectra obtained for each protein in two independent dissections. Sample #1 represents spectra for the interstitial amyloid deposits (B), and Sample #2 represents spectra for predominantly glomerular amyloid deposits (C) Amyloid‐related proteins are starred and shown at the top of the list. Proteins highlighted with double stars are universal amyloid signature proteins. Proteins highlighted with blue stars are type deterministic proteins. Sample #1 demonstrated exclusively lambda LC peptides, whereas Sample #2 showed three type deterministic proteins: Lambda LC, μ heavy chain, and GSN peptides. The low abundance of GSN spectra prohibited identifying the variant peptide.
Histological analyzes, immunogold electron microscopy, and proteomic detection of amyloidogenic proteins in the endomyocardial deposits in case 2. Congo red stain of endomyocardial tissue showing amyloid deposits viewed by light (A) and polarized (B) microscopy. Original magnification ×400. Electron micrographs showing haystack‐like organization of amyloid fibrils in the extracellular space of endomyocardial biopsy (C, D). Immunogold labeling demonstrating numerous electron dense deposits with antibody directed against immunoglobulin kappa LC (C) and TTR (D). Original magnification, ×40 000. Negative immunogold labeling results for immunoglobulin lambda LC and amyloid A are not shown. Scaffold display of the top 10 proteins identified in the endomyocardial amyloid deposits (E). Congo red positive areas of the endomyocardial biopsy were laser microdissected and subjected to LC–MS/MS analysis. Two independent microdissections were performed. Proteins highlighted with blue star denote type deterministic proteins. Proteins highlighted with orange and blue stars represent universal amyloid signature proteins. Numbers in green boxes denote the total number of tandem MS/MS spectra obtained for each protein in independent dissections, representing a semiquantitative measure of protein abundance. Three type deterministic proteins, kappa LC, μ heavy chain, and TTR, were detected in the amyloid deposits. There was no evidence of lambda LC or other known amyloidogenic precursor proteins in the specimens.
Histological analyzes, immunogold electron microscopy, and proteomic identification of lambda LC and TTR proteins in the amyloid deposits in case 3. Congo red stain of fat tissue showing amyloid deposits viewed by light (A) and polarized (B) microscopy. Original magnification ×100. Electron micrographs showing haystack‐like organization of amyloid fibrils in the extracellular space of fat pad aspirate (C–F). Immunogold labeling demonstrating numerous electron dense deposits with antibody directed against immunoglobulin lambda LC (C) and no immunoreactivity with antibody against immunoglobulin kappa LC (D), transthyretin (E), or amyloid A (F). Original magnification, ×40 000. Scaffold display of the top 10 proteins identified in the large bowel and renal amyloid deposits (G). Congo red positive areas of the large bowel and kidney biopsies were laser microdissected and subjected to LC–MS/MS analysis. Two independent microdissections were performed for each specimen. Proteins highlighted with blue star denote type deterministic proteins. Proteins highlighted with orange and blue stars represent universal amyloid signature proteins. Numbers in green boxes denote the total number of tandem MS/MS spectra obtained for each protein in independent dissections, representing a semiquantitative measure of protein abundance. TTR peptides were identified exclusively in the bowel specimen (Sample #1 and Sample #2), and lambda LC peptides were identified exclusively in the renal specimen (Sample #3 and Sample #4). No other known amyloidogenic precursor proteins were present in the specimens.
Histological analyzes, immunogold electron microscopy, and proteomic identification of lambda LC and TTR proteins in the endomyocardial amyloid deposits in case 4. Congo red stain of fat pad aspirate (A, B) and endomyocardial tissue (C, D) showing amyloid deposits viewed by light (A, C) and polarized (B, D) microscopy, respectively. Original magnifications ×100 (A, B) and ×20 (C, D). Electron micrographs showing haystack‐like organization of amyloid fibrils in the extracellular space of fat pad aspirate and endomyocardial biopsy (E–H). Immunogold labeling demonstrating numerous electron‐dense deposits (i) in the fat aspirate with antibody directed against immunoglobulin lambda LC (E, original magnification, ×60 000), and no immunoreactivity with antibody against transthyretin (F, original magnification, ×40 000) and (ii) in the endomyocardial biopsy with antibody directed against TTR (G, original magnification, ×50 000) and no immunoreactivity with antibody against immunoglobulin lambda LC (H, original magnification, ×50 000). Negative immunogold labeling results for immunoglobulin kappa LC and amyloid A in the fat aspirate and endomyocardial biopsy are not shown. Scaffold display of the top 10 proteins identified in the endomyocardial amyloid deposits (I). Congo red positive areas of the endomyocardial biopsy were laser microdissected and subjected to LC–MS/MS analysis. Two independent microdissections were performed. Protein highlighted with orange star denotes type deterministic protein. Proteins highlighted with orange and blue stars represent universal amyloid signature proteins. Numbers in green boxes denote the total number of tandem MS/MS spectra obtained for each protein in independent dissections, representing a semiquantitative measure of protein abundance. Exclusively TTR peptides were identified in the endomyocardial biopsy. No other known amyloidogenic precursor proteins were present in the specimen.
Histological analysis and proteomic identification of AA and TTR proteins in fat aspirate amyloid deposits in case 5. Congo red‐stained fat pad aspirate showing interstitial (A) and vascular (B) amyloid deposits under fluorescent light. Original magnification ×100. Proteomic detection of amyloid A and TTR proteins in fat pad amyloid deposits (C). Scaffold readout of the top 10 proteins identified by LC–MS–MS in Congo red‐positive areas of fat pad aspirate. The number in the box denotes the total number of detected MS/MS spectra obtained for each protein in two independent dissections. Sample #1 represents spectra for the interstitial amyloid deposits (A) and Sample #2 represents spectra for the vascular amyloid deposits (B). Proteins highlighted with orange stars denote type deterministic proteins. Proteins highlighted with orange and blue stars represent universal amyloid signature proteins. Numbers in green boxes denote the total number of tandem MS/MS spectra obtained for each protein in independent dissections, representing a semiquantitative measure of protein abundance. Interstitial deposits (Sample #1) show predominantly TTR with only a minor component of amyloid A peptides, whereas vascular amyloid deposits (Sample #2) demonstrate the predominance of amyloid A compared to TTR peptides. There was no evidence of other known amyloidogenic precursor proteins in deposits.
The Amyloidosis Intersection: Dual Amyloid Types in a Single Host
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June 2025

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4 Reads

Background Advances in fibril typing by mass spectrometry have improved the accuracy of amyloidosis diagnosis. Dual amyloidogenic proteins have been reported in deposits in sole and multiple different organs. Methods Five patients with dual amyloidoses were diagnosed between 1995 and 2022 by Congo red staining and fibril typing using the best available methods at the time of evaluation. Sequencing of TTR and GSN genes was performed. Literature search identified 46 additional cases. Results Three patients exhibited Waldenström macroglobulinemia‐associated AL (n = 3) amyloidoses in conjunction with ATTRwt or AGel amyloidosis; two patients featured AL/ATTRwt and AA/ATTRwt amyloidoses. One patient demonstrated dual amyloidoses within one anatomical site; three patients featured two amyloidosis types at different anatomical sites; and one patient had dual amyloid deposits in a single anatomical site along with different sites. The time interval between diagnoses was 0–288 months, with the heart and kidneys being the most affected organs. Conclusions Our findings underscore the complexity of clinical presentation in amyloidosis, as multiple amyloid types can co‐exist in a single individual and affect various anatomical sites. Accurate assessment of the clinical phenotype and thorough amyloid fibril typing from the target organs are essential for precise diagnosis and tailored treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT00898235


Kaplan–Meier survival curves for liver disease. (A) By HCV infection status. (B) By lifetime serum ferritin level. HCV, hepatitis C virus.
Probability of liver disease by lifetime serum ferritin level.
Kaplan–Meier survival curves for liver disease by co‐existence of both HCV infection and lifetime serum ferritin level > 1500 ng/mL. HCV, hepatitis C virus.
ALT levels per individual patient over the period of observation (n = 248). ALT, alanine aminotransferase; ULN, upper limit of normal.
Lifetime Risk of Liver Disease in Patients With β‐Thalassemia: Data From the de‐LIGHT Retrospective Cohort Study

Background Liver disease is common in patients with β‐thalassemia, but data on lifetime incidence and risk factors are limited. Methods We conducted a retrospective cohort study of 557 patients with β‐thalassemia followed from diagnosis for a median of 38 years. Predictive, survival, and regression analyses were used to determine the association between liver disease and potential risk factors. Results The crude incidence of liver disease was 26.4% (fibrosis/cirrhosis 24.2%, median age 34.4 years; hepatocellular carcinoma 2.3%, median age 45.4 years, 38.5% not preceded by cirrhosis). Among evaluated risk factors, only hepatitis C virus (HCV) infection (adjusted hazard ratio [HR]: 2.195, p < 0.001) and lifetime serum ferritin level (adjusted HR per 100‐ng/mL increase: 1.030, p < 0.001) were significantly associated with liver disease, with a lifetime serum ferritin level > 1500 ng/mL being the best predictor (p = 0.001). Liver disease‐free survival was significantly shorter in patients who had both versus either or neither risk factor (p < 0.001). Mostly severe and persistent but not mild–moderate or temporary/fluctuating elevation in liver enzymes was associated with liver disease development. Conclusion Patients with β‐thalassemia have a considerably increased lifetime risk of liver disease that is primarily driven by HCV infection and/or uncontrolled iron overload, especially in the 4th–5th decades of life.


Geographical distribution of surgeons participanting to the online survey.
Four scenarios are presented: (1) Tumor located at the confluence of the three hepatic veins; (2) major liver tumor with satellite lesion; (3) tumor located at the portal bifurcation; and (4) tumor located at the hilar plate. For each scenario, the cumulative number of multiple versus single responses (line a) and of responses in favor of liver transplantation (LT) or liver resection (line b) are reported. In line c, indications to LT or resection are analyzed by dividing respondents into two groups (transplant surgeons vs. non‐transplant surgeons). For each scenario, the p value between the two subgroups is calculated. SHV, suprahepatic veins.
Open Questions in Surgery for Hepatoblastoma: A Joined SIOPEL‐IPSO Survey

June 2025

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14 Reads

Introduction Surgery is pivotal in the management of hepatoblastoma (HB) although approaches and techniques may vary. The Liver Group of the International Society of Pediatric Oncology (SIOPEL) and the International Pediatric Surgical Oncology (IPSO) group collaborated to develop an online survey to investigate specific technical aspects and challenging indications for HB surgery, with the goal of establishing shared guidelines. Methods An electronic survey with 50 items was developed to address preoperative assessment and specific surgical issues. All questions were multiple‐choice, allowing for multiple answers in complex cases. The survey was distributed via the SIOPEL and IPSO mailing lists. Results Overall, 10% of the mailing lists participated (52 respondents), including 28 transplant (LT) surgeons and 24 non‐LT surgeons from 25 countries, globally. Around 40% (20/52) work in high‐volume centers (> 10 hepatic resections/year, and > 10 liver transplants/year). For a mass at the origin of the suprahepatic veins, LT is preferred over resection (48 vs. 12), while a mass with satellite nodules favors liver resection (52 vs. 15). Non‐LT surgeons prefer LT for masses at the hilar plate, whereas LT surgeons choose resection (p < 0.05). IVC replacement is favored by transplant surgeons in case of infiltration (p = 0.043), mostly with heterologous venous grafts (p = 0.004). Discussion The heterogeneity of responses underscores the lack of a standardized approach to the various surgical scenarios encountered in the surgical management of HB. Further analysis will enhance the understanding of how different management strategies affect outcomes and promote the creation of evidence‐based guidelines for HB resection practices.


ROC curve analysis of methylation panel in peripheral blood.
The relationships between peripheral blood methylation panel and the proportion of bone marrow immature cells as well as the number of peripheral blood white blood cells.
Relationship between peripheral blood methylation panel and bone marrow chromosomal abnormalities, MRD and therapy. (A) The relationship between peripheral blood methylation panel and bone marrow chromosomal abnormalities. (B) The relationship between peripheral blood methylation panel and MRD after induction therapy. (C) The relationship between peripheral blood methylation panel and transplant therapy. (D) Quantitative changes in peripheral blood gene methylation before and after the initial treatment.
Diagnostic and Prognostic Significance of Peripheral Blood RASSF1A, P16, and PTGER4 Gene Methylation in Adult Acute Leukemia

Adult acute leukemia is a common hematopoietic malignancy. Current diagnostic methods have limitations, and there is a need for non‐invasive early diagnosis and follow‐up monitoring. This study aimed to evaluate the diagnostic and prognostic significance of peripheral blood RASSF1A, P16, and PTGER4 gene methylation in adult acute leukemia. From January 2023 to December 2024, 78 adult acute leukemia patients and 25 controls were enrolled. Peripheral blood samples were collected before chemotherapy and 30 days after initial treatment for gene methylation analysis. The results showed that the combined detection of these three genes had a diagnostic sensitivity of 82.1% and a specificity of 92.0%. Positive methylation was significantly associated with a higher proportion of bone marrow immature cells, chromosomal karyotype abnormalities, and a greater likelihood of bone marrow transplantation. After 30 days of initial treatment, peripheral blood gene methylation levels decreased significantly. In conclusion, the combined detection of peripheral blood gene methylation can identify high‐risk acute leukemia patients, serve as a prognostic marker, and be used for post‐treatment follow‐up monitoring.


(A) Treatment exposure and overall survival. Overall survival depicted next to number of days of exposure to TCP, ATRA, and LDAC. For patient 01‐013 last documented intake dates of TCP and ATRA were taken. For patient 02‐001 last documented intake date of ATRA was taken. Exact dates of last intake are unknown for both patients. Interruptions are due to protocol, adverse events, or other reasons. The allocated dose level of each patient is depicted (L1‐4); if the allocated dose level was not reached, the highest achieved dose level is shown in parenthesis. (B) Kaplan–Meier plot. Overall survival rate estimated by Kaplan–Meier method. The median OS was 62 days. The number at risk is shown below the graph.
In vivo induction of CD38 protein expression on AML blasts. The images depict formalin‐fixed, paraffin‐embedded bone marrow trephine biopsy samples obtained from patient 01‐013 (DL 4). (A) The picture shows the NACE (Naphthol‐AS‐D Chloroacetate‐esterase) labeling of formalin‐fixed paraffin embedded bone marrow trephine biopsy samples (magnification 40X). Panel A represents the pretreatment sample, while panel B shows the post‐treatment (after 1 cycle on day 28) sample. There are repressed granulopoiesis (marked with white asterisks) and massive blast cell infiltration (> 90%) (marked with white arrows) on both panels. (B) The picture shows the CD38 labeling of formalin‐fixed paraffin embedded bone marrow trephine biopsy samples (magnification 40X). Panel A represents the pretreatment sample, while panel B shows the post‐treatment (after one cycle on day 28) sample. On panel A, low CD38 expression on the blast cells (marked with white arrows) is seen, while panel B shows strong expression of CD38 on the blast cells. As an internal positive control, plasma cells have been used (marked with white asterisks). (C) IHC staining intensity in bone marrow. Immunohistochemical analysis of bone marrow biopsies, collected from nine patients both pretreatment and postfirst cycle of therapy. Staining intensity categorized into 5 groups: weak—1, weak/moderate—2, moderate—3, moderate/strong—4, and strong—5.
TCP plasma levels. TCP dose taken in the morning with patients' serum levels prior and two hours after intake with medians. Levels were measured at days 10, 20, 28, and 56. TCP was taken in the morning and evening as per protocol. Serum levels of TCP were quantified using a validated high‐performance liquid chromatography (HPLC) method coupled with tandem mass spectrometry (MS/MS).
Treatment‐induced in vivo changes in global transcriptomics (serially purified peripheral blood AML blasts) (A, B) Volcano plot and Heatmap of differentially expressed genes (DEGs) (FDR < 0.05 & Log2foldchange > 0.6) in patient 05‐001 (dose level 2, treated for 78 days). (C) GSEA enrichment of transcriptome on ‘KEGG 2021 Human’ database. (D, E) Volcano plot and Heatmap of DEGs (FDR < 0.05 & Log2foldchange > 0.6) in patient 01‐002 (dose level 1, treated for 50 days). (F, G) Regulation of known LSD1‐regulated genes in patient 05‐001 (F) and patient 01‐002 (G).
Sensitization of Non‐M3 Acute Myeloid Leukemia Blasts to All‐Trans Retinoic Acid by the LSD1 Inhibitor Tranylcypromine: TRANSATRA Phase I Study

June 2025

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20 Reads

The treatment of elderly, nonfit acute myeloid leukemia (AML)/MDS patients with relapsed/refractory (R/R) disease remains challenging. As histone demethylase LSD1 (KDM1A) is a rational therapeutic target in AML, we conducted a phase I trial (“rolling‐six design”) with the LSD1 inhibitor tranylcypromine (TCP, dose levels [DL] 20, 40, 60, 80 mg p.o. d1‐28) combined with fixed‐dose ATRA (45 mg/m² p.o. d10‐28) and low‐dose cytarabine (LDAC, 40 mg s.c. d1‐10). The primary endpoint was dose‐limiting toxicity (DLT) in the first 28 days of treatment. The aim was the determination of the maximum tolerated TCP dose (MTD). Twenty‐three patients with AML and 2 with MDS were accrued. TCP was administered for a median of 39.5 days (range: 11–228). No DLTs were observed at any DL; MTD could not be established. No differentiation syndrome occurred. Two patients attained a PR; SD was achieved in 10 of 22 evaluable patients. Median OS was 62 days (range: 14–325). Accompanying studies included pharmacokinetics, serial determinations of fetal hemoglobin (HbF), detection of CD38 upregulation with treatment, as well as transcriptome changes in purified blood blasts over time. In conclusion, the combination of TCP with ATRA and LDAC was well feasible, even at the highest DL. Hence, studies with more potent LSD1 inhibitors appear warranted. Trial Registration: German Clinical Trials Register (DRKS): DRKS00006055. For further Information see https://drks.de/search/en/trial/DRKS00006055


Progression‐free survival (A) and overall survival (B) after BR for NLPBL.
Efficacy and Safety of Bendamustine‐Rituximab for Nodular Lymphocyte Predominant Hodgkin Lymphoma

June 2025

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9 Reads

Introduction Bendamustine‐rituximab (BR) has demonstrated efficacy and tolerability in the treatment of various indolent B‐cell lymphomas, but there is limited data regarding its outcomes in nodular lymphocyte predominant B‐cell (Hodgkin) lymphoma (NLPBL). Methods This retrospective, population‐based study included consecutive patients ≥ 18 years old who received BR for NLPBL in Alberta, Canada. Results The study population comprised 23 patients with a median age of 39 years (range 18–74) who received BR for treatment‐naive (n = 17) or relapsed/refractory (n = 6) NLPBL. Advanced stage disease was present in 18 (78%), splenic involvement in 9 (39%), and bone marrow involvement in 8 (35%) patients. The response rate to BR was 100%, with a complete response in 78% and a partial response in 22%. After a median follow‐up of 4.3 years (range 0.8–9.0), the 4‐year progression‐free survival and overall survival rates were 83% (95% CI: 55%–94%) and 87% (95% CI: 58%–97%) for all patients and 84% (95% CI: 50%–96%) and 91% (95% CI: 51%–99%) for recipients of first‐line BR, respectively. The safety profile was in keeping with the known toxicities of BR, with the most common adverse events consisting of neutropenia, rash, and infusion reactions. Conclusion These findings suggest that BR is a promising treatment option for NLPBL, with a favorable efficacy and safety profile.


The clinical and Laboratory Features of VEXAS Syndrome. This figure incorporates images from Servier Medical Art, which is licensed under a Creative Commons Attribution 4.0 Unported License (CC BY). For more details, visit (https://smart.servier.com/citation‐sharing/) (https://creativecommons.org/licenses/by/4.0/).
Proposed algorithm for the diagnosis of BM vacuolization. Flow cytometric gating strategy for identifying neutrophils, monocytes, and erythroid precursors using Ding et al. method [44]:Neutrophils: Dot plots show neutrophils (blue) selected based on CD45 expression and side scatter (SSC) properties. The stages of neutrophil maturation are defined by CD11b and CD13 expression, ranging from the least mature (high CD13/low CD11b, violet) to the most mature (high CD13/high CD11b, orange). Monocytes: Monocytes (light red) are identified by their high CD64 expression and SSC properties. Immature monocytes are further distinguished by their low CD14 expression (green). Erythroid Precursors: Nucleated red blood cells (brown) are identified by strong CD71 expression and little to no CD45 expression. Early red cell precursors are characterized by high CD105 and relatively low glycophorin A expression (light blue). The histograms on the right depict SSC intensity for precursors: Neutrophil precursors (violet), monocyte precursors (dark green), and early red cell precursors (light blue). Lymphocytes are gated based on CD45 and SSC properties (dark blue). Abbreviations: AI; artificial intelligence, DAMPs; damage‐associated molecular patterns, ddPCR; Digital Droplet PCR, GNNs; Graph Neural Networks, HMGB1; high mobility group box 1, ML; Machine learning, NGS; Next‐Generation Sequencing, PNA; Peptide Nucleic Acid, scDNA‐seq; Clamping Single‐Cell DNA, scRNA‐seq; RNA Sequencing, SSCs; side scatters, VAF; variant allele frequency, WES; Whole‐Exome Sequencing, WGS; Whole‐Genome Sequencing.
Bone Marrow Vacuolization at the Crossroads of Specialties: Molecular Insights and Diagnostic Challenges

Bone marrow (BM) vacuolization is a key morphological feature observed in VEXAS (Vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome. However, vacuolization alone is not specific to VEXAS, as it can also be seen in conditions such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), metabolic disorders, and toxic exposures. VEXAS syndrome, a postzygotic mutation‐driven autoinflammatory disease caused by somatic mutations in the UBA1 gene, leads to chronic immune activation, clonal expansion of hematopoietic cells, and systemic inflammation. UBA1 mutations result in protein misfolding, contributing to both hematologic and inflammatory abnormalities. In VEXAS syndrome, specific features of vacuolated progenitor cells suggest the diagnosis. These include a high number of vacuolated cells, increased vacuoles per cell, a predominance of vacuoles in early progenitors rather than later stages, and vacuolization in both myeloid and erythroid progenitors, with myeloid progenitors most affected. However, the absence or low frequency of vacuolated cells should not rule out the possibility of VEXAS, and UBA1 gene sequencing should still be considered, especially in patients with unexplained systemic inflammation, MDS, or associated with other hematologic disorders. These mutations may alter the BM microenvironment, promoting the survival and expansion of mutant clones, which drive disease progression. While there is no standard treatment for VEXAS, the condition provides a unique model for understanding how inflammation in the BM microenvironment contributes to clonal selection and hematologic malignancy development. Research into the genetic and molecular mechanisms behind BM vacuolization in VEXAS has improved the diagnostic approaches and enhanced our understanding of its impact on hematopoiesis. Ongoing studies into the interplay between vacuolization, clonal hematopoiesis, and immune dysregulation will be a key to developing effective therapies for this complex syndrome. We herein offer a comprehensive diagnostic approach to BM vacuolization linked to VEXAS syndrome, distinguishing it from vacuoles observed in other conditions. The analysis delves into the clinical and hematologic features, molecular pathways, and rapidly evolving diagnostic methods for VEXAS syndrome, emphasizing its impact on hematopoiesis from a hematologic perspective.


Cumulative incidence of acute and chronic GVHD for PSM cohort.
Main outcomes for PSM cohort.
Impact of Conditioning Intensity on Survival in Adult Patients (< 65 Years) With Acute Myeloid Leukemia Receiving Antithymocyte Globulin and Post‐Transplantation Cyclophosphamide Based GVHD Prophylaxis

May 2025

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11 Reads

Introduction Myeloablative conditioning (MAC) for acute myeloid leukemia (AML) improves disease control by reducing relapse risk but is associated with higher non‐relapse mortality (NRM). Reduced‐intensity conditioning (RIC) aims to minimize toxicity but raises concerns about higher relapse rates. This study evaluates the impact of RIC versus MAC in AML patients under 65 years receiving GVHD prophylaxis with antithymocyte globulin, post‐transplant cyclophosphamide, and cyclosporine. Methods We retrospectively analyzed 322 AML patients undergoing allogeneic HCT with uniform GVHD prophylaxis. Propensity score matching (PSM) was applied to adjust for baseline differences. Results In the matched cohort, 2‐year overall survival (OS) did not differ significantly between RIC and MAC recipients (64.4% vs. 66.9%, p = 0.56). Relapse‐free survival (RFS) at 2 years was 65.0% for MAC and 52.7% for RIC (p = 0.20). Two‐year NRM was 19.4% for MAC and 19.1% for RIC (p = 0.84). Improved RFS was associated with non‐high‐risk DRI (HR: 0.39, p = 0.008), whereas conditioning intensity had no significant effect (HR: 0.98, p = 0.97). NRM was higher among patients with KPS < 90 (HR: 3.63, p = 0.01), with no significant impact observed from conditioning intensity (HR: 1.44, p = 0.43). Conclusion In a relatively younger cohort, conditioning intensity did not significantly impact survival, and MAC was not associated with increased NRM.


(A) Overall survival and (B) progression‐free survival in patients with GI‐DLBCL and those with non‐GI‐DLBCL. The competing risks of lymphoma relapse and non‐relapse mortality (NRM) between patients with GI‐DLBCL and those with a non‐GI‐DLBCL who achieved CR after (C) first‐line chemotherapy.
Overall survival and progression‐free survival according to Lugano stage in the gastric DLBCL group (A, B) and the intestinal DLBCL group (C, D).
(A) Overall survival, (B) progression‐free survival, and (C) the competing risks of secondary gastric cancer and death between patients with localized‐stage gastric DLBCL receiving CMT (chemotherapy + radiotherapy) vs. six cycles of chemotherapy.
Forest plots based on (A) OS and (B) PFS in the patients with localized‐stage intestinal DLBCL.
Site‐ and Stage‐Adapted Treatment Strategies for Gastrointestinal Diffuse Large B‐Cell Lymphoma

Objectives Although gastrointestinal diffuse large B‐cell lymphoma (GI‐DLBCL) is managed variously, the optimal approach remains controversial. Methods We retrospectively analyzed 701 patients with DLBCL at our institution between March 2004 and June 2024, including 160 with GI‐DLBCL. We compared baseline characteristics and survival outcomes of GI‐DLBCL with non‐GI‐DLBCL and further analyzed gastric and intestinal DLBCL by stage. Results No significant difference in survival outcomes was observed between GI and non‐GI DLBCL groups after a median follow‐up of 5.1 years. Among patients with gastric DLBCL, advanced disease was associated with poorer overall survival (OS) (hazard ratio [HR]: 1.75; 95% confidence interval [CI]: 1.18–2.58; p = 0.003) than localized disease. Similar findings were observed in intestinal DLBCL (HR: 1.60; 95% CI: 1.13–2.27; p = 0.006). Combined chemoradiation and chemotherapy yielded similar survival outcomes for localized gastric DLBCL although the former showed a higher cumulative incidence of secondary gastric cancer (p = 0.04). In localized intestinal DLBCL, multivariate analysis identified surgery followed by chemotherapy as a favorable prognostic factor for OS (HR: 0.23; 95% CI: 0.067–0.83; p = 0.024). Conclusions Gastrointestinal diffuse large B‐cell lymphoma had survival outcomes comparable to those of non‐GI‐DLBCL, suggesting site‐ and stage‐specific therapies may confer a survival benefit.


Flow diagram illustrating study population selection.
Forrest plot depicting adjusted analyses of outcomes in multiple myeloma admissions in aya and older adult population. aOR = adjusted odds ratio; AYA = adolescents and young adults; CI = confidence intervals; model adjusted for age, gender, race/ethnicity.
Characteristics and Clinical Outcomes of Multiple Myeloma in Adolescents and Young Adults

Introduction Though evidence suggests that multiple myeloma (MM) in adolescents and young adults (AYA) (< 50 years) has significant biological differences from that in older individuals (≥ 50 years), the understanding of the disease in this group is limited. We examined the outcomes in AYA hospitalizations with MM. Methods Using the National Inpatient Sample database, we examined sociodemographic, hospital‐level, and clinical characteristics between AYA and older populations with MM. Results Among 183 846 non‐elective MM hospitalizations, 13 765 (7.5%) were AYA. There was a higher proportion of males in the AYA group compared to the older group (58.6% vs. 54.8%, p < 0.001) but a lower distribution of non‐Hispanic Whites (40.6% vs. 56.7%, p < 0.001). The AYA group had lower odds of mortality (aOR: 0.59, p < 0.001) relative to the older adult group. They were more likely to receive autologous stem cell transplantation (aOR: 1.80, p < 0.001) but had similar odds of acute venous thromboembolism (aOR: 0.87; p = 0.24) and severe sepsis (aOR: 0.89; p = 0.52). Conclusion We highlight the unique characteristics and outcomes of AYA‐MM, emphasizing the need for their greater representation in clinical research. Additionally, we underscore the importance of further investigation to better understand and optimize survivorship care in AYA patients with MM.


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FIGURE 3
Gender Disparity in Enrollment in Clinical Trials for Hairy Cell Leukemia Treatments in the Last 40 Years

Background Hairy Cell Leukemia (HCL) is a B‐cell lymphoproliferative disorder that predominantly affects males, yet recent evidence suggests a notable gender participation gap in HCL clinical trials. This study aims to characterize that disparity and explore potential factors contributing to the under‐enrollment of females. Methods In this descriptive, retrospective study, we searched EMBASE, PUBMED, Cochrane Central, and ClinicalTrials.gov from January 1983 to December 2023 for publications on clinical trials (CT) in HCL, descriptive statistical analysis of all the sociodemographic variables was performed. Results We analyzed 57 clinical trials totaling 4595 HCL patients, with 79.1% male and 20.9% female participants. The male‐to‐female ratio declined from 5.91 (1983–1993) to 4.19 (2014–2023). Although the gender gap narrowed over time, female participation slightly decreased to 19.2% in the most recent period (2014–2023). Conclusions Female enrollment in HCL clinical trials remains disproportionately low compared to incidence rates, underscoring the need to address underlying barriers to improve equity in clinical research and treatment outcomes. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.



AEML in young adults (18–60 years). (A) Classification of the AEML patients according to ICC 2022 and WHO criteria (n = 41 patients for whom data were available) The categories of AML in the ICC and WHO classifications are colored grey. MDS or MDS/AML categories (for ICC) are in white. (B) Molecular landscape (performed for n = 43 patients). RAS pathway: NRAS, KRAS, PTPN11, RIT1, CBL; Cohesin: RAD21, SMC1A, SMC3, STAG2; Spliceosome: SF3B1, SRSF2, U2AF1, ZRSR2. (C) Disease‐free survival and (D) overall survival according to the blast infiltration above (AML) or below (oligo‐AML) 20% among total BM nucleated cells (n = 41 patients receiving intensive chemotherapy for whom data were available).
AEML with NPM1 mutations in young adults. (A) May‐Grünwald‐Giemsa‐stained bone marrow smear in a 40‐year‐old female patient with NPM1 mutation (VAF 46%). The complete blood count showed pancytopenia (WBC 4.6 × 10⁹/L, hemoglobin 7.3 g/dL, platelets 89 × 10⁹/L). The bone marrow (performed twice with reproducible results) showed 6% myeloid blasts with erythroid hyperplasia (72% erythroblasts) and dysmyelopoiesis. (B) Pattern of co‐mutations in NPM1‐mutated AML according to the FAB subtype. (C) Disease‐free survival and (D) overall survival in AEML/M6‐FAB AML with NPM1 mutation compared to non‐M6‐FAB AML with NPM1 mutations.
Myeloid Neoplasms With Erythroid Predominance and Excess Blasts in Young Adults Exhibit Distinct Genetic Profiles

May 2025

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69 Reads

The evolution of acute myeloid leukemia (AML) classifications has progressively shifted the diagnostic focus toward genetic criteria. Nevertheless, morphology remains a key element in clinical practice, often serving as the initial trigger for additional molecular investigations. The diagnosis of acute erythroleukemia (AEML), initially defined by the FAB group, is no longer recognized as a distinct entity in the latest WHO and ICC classifications. Some studies have indicated that AEML shares similarities with myelodysplastic neoplasms, including a high frequency of TP53 mutations and adverse karyotypes. Here, we conducted a retrospective analysis in adults with AEML defined using historical morphologic criteria (≥ 50% erythroid precursors and ≥ 20% blasts among non‐erythroid cells). In contrast to older patients, young adults (18–60 years) exhibit unique genetic profiles including a high prevalence of normal karyotypes (65%), NPM1 (35%) and UBTF (23%) mutations. AEML morphology in NPM1‐mutated cases did not impact clinical outcomes but was associated with specific molecular features, including an enrichment of WT1 and cohesin gene mutations. In this age group, our findings support that morphologically defined AEML often corresponds to AML according to current genetic criteria, consistent with recent classification systems that prioritize molecular features over morphology.


The flowchart illustrates the process of using CNNs for the classification of B‐ and T‐cell lymphomas in this study. In (a), pathologic tissue slides of B‐ and T‐cell lymphoma are photographed and scanned to produce digital images, which are then used to train four pre‐trained CNN models, which are subsequently used to classify new images as either B‐ or T‐cell lymphomas. (b) Details the dataset handling and model development workflow, beginning with data gathering from three hospitals for training, validation, and testing, respectively. The datasets undergo preprocessing steps including augmentation and resizing, followed by transfer learning for model development. The models are optimized through the modification of layers, loss function, and global optimization. The pre‐trained model pool, consisting of Xception, NASNetL, ResNet‐50, and EfficientNet, is utilized for the final classification task.
The CBAM enhances feature extraction by sequentially applying two key attention mechanisms: The Channel Attention Module (CAM) and the Spatial Attention Module (SAM). As depicted in the figure, CAM operates first by processing the input feature map through two global pooling operations, GAP and global max pooling (GMP), which capture different aspects of the feature information. These pooled outputs are then passed through a shared Multi‐Layer Perceptron (MLP), followed by element‐wise summation and a Sigmoid function to generate the channel attention map, which emphasizes important channels by modulating the original feature map. Next, the SAM refines the feature map further by focusing on “where” the important features are located spatially. It applies average and max pooling across the channel dimensions to generate two 2D feature maps, which are concatenated and passed through a convolution layer. The output of the convolution is activated with a Sigmoid function, producing the spatial attention map, which is multiplied with the feature map to refine the spatial focus of the network, resulting in enhanced feature representation.
Comparison of attention maps obtained from the last layer of various learning models for representative images of Grad‐CAM in B‐ and T‐cell lymphoma.
Learning‐Based Classification of B‐ and T‐Cell Lymphoma on Histopathological Images: A Multicenter Study

Lymphoma, a clonal malignancy from lymphocytes, includes diverse subtypes requiring distinct immunohistochemical stains for accurate diagnosis. Limited biopsy specimens often restrict the use of multiple stains, complicating diagnostic workflows. Lymphomas are typically classified into B‐cell and T‐cell types, each with specific markers. This study represents the first feasibility study in deploying deep learning models for B‐ and T‐cell lymphoma classification on histopathological images. We analyzed 1510 H&E‐stained sections (750 B‐cell, 760 T‐cell) with CNN models (Xception, NASNetL, ResNet50, EfficientNet), enhanced by Convolutional Block Attention Modules (CBAMs). All models demonstrated strong classification capabilities, with EfficientNet achieving the highest accuracy at 91.5% and the best precision at 91.9%, while Xception performed the best recall at 91.5%. Furthermore, the deep learning models significantly outperformed human pathologists in classification accuracy and inference speed, processing images in milliseconds compared to the several seconds required for manual diagnosis. These findings underscore the effectiveness of advanced CNN models in improving diagnostic precision while reducing dependency on manual staining and interpretation, and the integration of AI‐driven classification can provide valuable support for pathologists.


Flow chart of HK‐AML patient selection and subgrouping. Adverse karyotype abnormalities are based on 2022 ELN risk classification. † Excluded patients with inv(16), t(8;21), and t(15;17).
Karyotype features of HK‐AML cases (A) Modal chromosome number in subgroups of HK‐AML (B) Chromosome gain and loss pattern in subgroups of HK‐AML.
Mutation landscape of HK‐AML patients. NGS results are available for 8 HK‐NUM, 9 HK‐STR and 28 HK‐ADV cases. (A) Oncoprint of comutation in study population. Genes are listed at left. Percentages of patients' carrying mutations in different genes (at right) as well as variant allele frequency (VAF) are shown. Numbers of genes mutated in each case are shown on the top and HK‐AML subgroup, age, and gender information are at the bottom. (B) Number of genes mutated distribution in each subgroup of HK‐AML. (C) Correlation plot of the mutated genes. indicates positive correlation is shown by blue and negative correlation is shown by red. Values represent the coefficients and significant pairs are shown.
Kaplan–Meier survival plots comparing the outcome in HK‐AML patients. (A) Overall survival (OS) and event‐free survival (EFS) in three subgroups of HK‐AML patients. (B) Effect of allogeneic hematopoietic stem cell transplantation (HCT) on OS and EFS in HK‐AML patients. (C) OS and EFS in three subgroups of HK‐AML patients in comparison with AML, NOS with normal karyotype group (NK‐AML‐NOS). (D) Effect of modal chromosome number on OS and EFS in HK‐AML patients.
Genetic Landscape and Risk Stratification of AML With Hyperdiploid Karyotype

May 2025

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13 Reads

Hyperdiploid karyotype (HK) (49–65 chromosomes) in acute myeloid leukemia (AML) is rare. Recently, HK‐AML with only numerical changes has been reclassified into an intermediate risk group in the updated 2022 European LeukemiaNet (ELN) risk classification, which has historically been classified into an adverse risk group. However, there are limited data in the literature concerning whether these new exclusion criteria are appropriate, and the genetic landscape of HK‐AML remains unclear. We retrospectively analyzed a cohort of HK‐AML diagnosed at our institution. Among 124 cases, 72 (58.1%) had concurrent adverse risk cytogenetic abnormalities (HK‐ADV), 33 (26.6%) had other concurrent structural abnormalities (HK‐STR) and 19 (15.3%) had numerical changes alone (HK‐NUM). The most frequently gained chromosomes were chromosomes 8, 22, 21, and 19. TP53 mutation was associated with HK‐ADV, and a higher frequency of mutations in DNA methylation genes was present in HK‐NUM and HK‐STR. Patients with HK‐NUM had significantly longer overall survival (OS) and event‐free survival (EFS) compared to those with HK‐ADV. In the adjusted model accounting for confounders, the HK‐STR outcome was superior to that of HK‐ADV but was not significantly different from that of HK‐NUM. In addition, patients with a modal chromosome number of 49–53 had more favorable survival than those with ≥ 54 chromosomes. Our data support the reclassification of HK‐NUM patients in the intermediate risk group and suggest that HK‐STR might also be more appropriately classified into the intermediate risk group.


Distribution of ferritin‐index in relation to sex, N = 439 (181 women, 258 men), three outliers with high ferritin indices are not visible in the graphic (21.6, 28.01, and 90.54).
Violin plot age distribution by sex and presence of ID (ferritin index ≥ 1.5), white diamond = median.
Iron Deficiency in the Presence of Anemia and Inflammation—A Sex‐Specific Cross‐Sectional Study

Objectives Despite frequent diagnosis of anemia of inflammation in hospitalized patients, little is known about patients' sex‐specific differences in iron deficiency (ID) and its biomarkers. We aimed to study sex‐specific differences in anemic patients with inflammation and their influence on iron biomarkers. Methods This retrospective cross‐sectional study included anemic patients with inflammation (CRP > 5 mg/L) hospitalized at a Swiss tertiary referral center (01.01.2020–31.12.2023). ID was defined as ferritin‐index (sTfR/log(ferritin)) ≥ 1.5. Patient characteristics were reported as medians for continuous variables and frequencies for categorical variables. Age, laboratory parameters, treatment, comorbidities, illness severity, and in‐hospital mortality were analyzed. Sex‐specific effects on ID biomarkers (ferritin‐index, sTfR) were assessed using linear regression models. Results Of 439 participants, 41.2% were female. 44.2% had ID (women: 49.7%, men: 40.3%, p = 0.052). Regression models showed no association between log(ferritin‐index) and sex (coefficient 0.02, 95% CI −0.13 to 0.18, p = 0.76). Ferritin levels were lower in women (221.0 vs. 373 μg/L, p = 0.014). No sex differences in in‐hospital mortality were observed (women 7.2%, men 4.3%, p = 0.21). Conclusions Despite no significant sex differences regarding ID biomarkers, treatment, illness severity, and mortality, we hypothesize that factors beyond sex, for example underlying diseases and inflammation itself, play a more prominent role in these patients' outcomes.


PRISMA flow diagram. DLBCL = diffuse large B‐cell lymphoma; EMM = effect measure modifier; NR = not reported; PF = prognostic factor. aSearch was conducted on December 13, 2021.
Prognostic Factors and Effect Modifiers in Patients With Relapse or Refractory Diffuse Large B‐Cell Lymphoma After Two Lines of Therapy: A Systematic Literature and Expert Clinical Review

Objectives The objective of this systematic literature review (SLR) combined with expert clinical review was to identify and rank prognostic factors and effect measure modifiers (EMMs) systematically and comprehensively in patients with relapsed or refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) who initiate treatment after ≥ 2 prior lines of therapy (LoTs; 3L+ R/R DLBCL). Methods We performed an SLR of studies published between 2016 and 2021 and extracted study characteristics, prognostic factors, and EMMs. This was followed by clinical review and ranking of findings by subject matter experts using questionnaires, follow‐up interviews, and quantitative ranking. Results Across 46 included studies, the SLR identified 36 prognostic factors significantly associated with ≥ 1 clinical outcome. Based on subject matter expert ranking of the SLR‐derived list, the five most important prognostic variables in descending order are: early chemo‐immunotherapy failure, Eastern Cooperative Oncology Group performance status, refractory to last LoT, number of prior LoTs, and double‐ or triple‐hit lymphoma. Conclusions This SLR and expert clinical review is the first to provide a comprehensive assessment of prognostic factors for 3L+ R/R DLBCL. No statistically significant EMMs were identified. This robust multi‐method approach can assist in selecting prognostic variables for comparative analyses between real‐world studies and clinical trials.



Clinical outcomes (a) Overall survival, (b) Graft‐versus‐host disease/relapse‐free survival, (c) Non‐relapse mortality, (d) Cumulative incidence of relapse.
Clinical outcomes between patients receiving post‐transplant cyclophosphamide vs. others—(a) Overall survival, (b) Graft‐versus‐host disease/relapse‐free survival, (c) Non‐relapse mortality, (d) Cumulative incidence of relapse.
Graft‐versus‐host disease—(a) acute GvHD grade II‐IV, (b) acute GvHD grade II‐IV (with and without PTCy), (c) acute GvHD grade III‐IV, (d) acute GvHD grade II‐IV (with and without PTCy), (e) Moderate–severe chronic GvHD, (f) Moderate–severe chronic GvHD (with and without PTCy).
Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic/Myeloproliferative Overlap Neoplasms

Myelodysplastic/myeloproliferative overlap neoplasms (MDS/MPN) are rare hematological malignancies. We analyzed the outcomes of 75 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for MDS/MPN. Graft‐versus‐host disease (GvHD) prophylaxis included post‐transplantation cyclophosphamide (PTCy) in 71% of patients, with 44 (59%) receiving a combination of anti‐thymocyte globulin (ATG) and PTCy. The median follow‐up was 44.4 months. Primary graft failure occurred in three patients (4%). The incidence of grade III‐IV acute GvHD at day 100 was 13% (95% CI: 6–22). At 2 years, the incidence of moderate–severe chronic GvHD, non‐relapse mortality (NRM), relapse, GvHD‐free/relapse‐free survival (GRFS), and overall survival (OS) was 31.7% (95% CI 20.7–43.2), 37.9% (26–49), 17.4% (95% CI: 10–27), 24.8% (95% CI: 15–36), and 51.6% (95% CI: 39–63), respectively. PTCy‐based GvHD prophylaxis seemed to be associated with improved OS (HR: 0.5, 95% CI: 0.3–0.9, p = 0.03), NRM (HR: 0.4, 95% CI: 0.2–0.9, p = 0.03), and GRFS (HR: 0.5, 95% CI: 0.3–0.8, 0.009). On multivariable analysis, the use of the PTCy‐containing regimen seemed to be associated with improved NRM (HR: 0.41; 95% CI: 0.2–0.8; p = 0.03), GRFS (HR: 0.47; 95% CI: 0.3–0.8; p = 0.009), and OS (HR: 0.49; 95% CI: 0.2–0.9; p = 0.03) without an increased risk of relapse.


ITI outcomes for first‐time ITI patients receiving rFVIIIFc. ITI: immune tolerance induction; rFVIIIFc: recombinant factor VIII Fc fusion protein.
rFVIIIFc usage in first‐time ITI patients (n = 24). Percentages may not sum to 100 due to rounding. ITI: immune tolerance induction; IU: international unit; rFVIIIFc: recombinant factor VIII Fc fusion protein.
ITI outcomes for rescue ITI patients receiving rFVIIIFc. ITI: immune tolerance induction; rFVIIIFc: recombinant factor VIII Fc fusion protein.
rFVIIIFc usage in rescue ITI patients (n = 17). ITI: immune tolerance induction; IU: international unit; rFVIIIFc: recombinant factor VIII Fc fusion protein.
Immune Tolerance Induction With a Recombinant Factor VIII Fc in Haemophilia A: Data From a Chart Review Study

April 2025

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19 Reads

Objective To report data from an ITI chart review study (NCT03951103) for first‐time and rescue ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in persons with haemophilia A. Methods Retrospective and prospective real‐world data are reported from a non‐interventional, multicentre study of patients who had been or were currently being treated with rFVIIIFc ITI. ITI treatment outcome (defined by investigators) and regimens are reported. Results Forty‐one patients from 16 sites were included. First‐time ITI was used in 24 patients; 16 had an ITI outcome at study end. Thirteen patients (81.3%) had ITI success, and three had failure. Median (range) rFVIIIFc consumption was 300 (61–2800) IU/kg/week, and most (70.8%) used ≤ 300 IU/kg/week. The vast majority of patients (87.5%) received less than daily ITI. Rescue ITI was used in 17 patients; 16 had an ITI outcome at study end. Eight patients (50.0%) had ITI success/partial success, seven had failure, and one withdrew early. Median (range) rFVIIIFc consumption was 536 (98–1435) IU/kg/week; 35.3% used ≤ 300 IU/kg/week and 52.9% used > 500 IU/kg/week. Most patients (64.7%) received daily ITI. Conclusion ITI with rFVIIIFc is likely to be successful in first‐time ITI patients and is an effective option for those who have previously experienced ITI failure. Trial Registration: ClinicalTrials.gov identifier: NCT03951103


Mean difference in change‐from‐baseline to EOS in Hb level (g/dL; increase) between pegcetacoplan and iptacopan, respectively, versus C5i. CI, confidence interval; EOS, end of study; Hb, haemoglobin; IPT, iptacopan; PEG, pegcetacoplan.
Mean difference in change‐from‐baseline to EOS in ARC (10⁹/L; decrease). ARC, absolute reticulocyte count; CI, confidence interval; EOS, end of study; IPT, iptacopan; PEG, pegcetacoplan.
Mean difference in change‐from‐baseline to EOS in LDH level (IU/L; decrease) between pegcetacoplan and iptacopan, respectively, versus C5i. CI, confidence interval; EOS, end of study; IPT, iptacopan; LDH, lactate dehydrogenase; PEG, pegcetacoplan.
Mean difference in change‐from‐baseline to EOS in FACIT‐Fatigue score (increase) between pegcetacoplan and iptacopan, respectively, versus C5i. CI, confidence interval; EOS, end of study; FACIT‐Fatigue, Functional Assessment of Chronic Illness Therapy—Fatigue; IPT, iptacopan; PEG, pegcetacoplan.
Anchored Indirect Treatment Comparison Finds Comparable Effects of Pegcetacoplan and Iptacopan in Paroxysmal Nocturnal Haemoglobinuria

April 2025

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11 Reads

Background Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra‐rare, acquired non‐malignant haematological disorder characterised by thrombosis risk, serious complications and debilitating symptoms in untreated patients. Objective This anchored indirect treatment comparison (ITC) evaluated efficacy data between proximal complement 3 inhibitor (C3i) pegcetacoplan and factor B inhibitor, iptacopan, in patients with PNH previously treated with complement 5 inhibitors (C5i; eculizumab, ravulizumab). Methods Respective pivotal studies provided patient‐level trial data for pegcetacoplan (16‐week PEGASUS [NCT03500549]) and published data for iptacopan (24‐week APPLY PNH [NCT04558918]). Differences in study design, duration and statistical methods between PEGASUS and APPLY PNH necessitated the comparative analyses to be conducted on secondary measures based on haemoglobin (Hb) levels, absolute reticulocyte count (ARC), lactate dehydrogenase (LDH) levels, and patient‐reported outcomes on the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐Fatigue) scale scores. The availability of a common reference C5i treatment group in both PEGASUS and APPLY PNH studies allowed anchored ITC (Bucher method). Simulated treatment comparison (STC) assessed the robustness of the main analysis. Results Overall, baseline characteristics of the populations in the PEGASUS and APPLY PNH studies were broadly comparable. Anchored ITC showed comparable outcomes (mean difference, [95% CI]) on change‐from‐baseline to end of study for pegcetacoplan versus C5i, and iptacopan versus C5i, respectively, across endpoints: Hb level (−0.49 g/dL [−1.78, 0.80]); ARC (–34.41 × 10⁹/L [−90.02, 21.21]); LDH level (−115.16 U/L [−244.40, 14.01]); FACIT‐Fatigue score (3.57 [−5.60, 12.73]). Finally, the STC produced results consistent with the main Bucher analyses across all clinical endpoints and patient‐reported fatigue, providing similar point estimates and confidence intervals. Conclusion This anchored ITC, based on data from pivotal trials, did not indicate significant differences in clinical or patient‐reported outcomes between pegcetacoplan and iptacopan in PNH treatment. The findings suggest that PNH treatment decisions should also consider individualised disease‐ and patient‐related factors. Trial Registration: ClinicalTrials.gov identifier: NCT03500549.


Weight loss over time EN versus PN. p = NS for all variables. SGA, Subjective Global Assessment; SGA‐A, well‐nourished; SGA‐B, mild‐moderately malnourished; SGA‐C, severely malnourished. p = NS.
SGA at Day 15, EN compared to PN. SGA, Subjective Global Assessment; SGA‐A, well‐nourished; SGA‐B, mild‐moderately malnourished; SGA‐C: severely malnourished. None of the patients at Day 15 were classified as severely malnourished. No SGA was completed at Day 30. p = NS for all variables.
Medical and Nutritional Outcomes Are Similar Among Autologous Transplant Patients on Enteral Nutrition When Compared to Parenteral Nutrition. A Randomized Pilot Study

April 2025

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8 Reads

Autologous hematopoietic stem cell transplantation (AHSCT) is the treatment for myeloma and lymphoma. posttreatment, significant nutritional and medical issues and malnutrition assessed by Subjective Global Assessment (SGA) arise. No established effective treatment for using either parenteral (PN) or enteral routes (EN) to improve nutritional status, reduce medical complications, and be cost‐effective is available. We investigated the effectiveness of EN versus PN in terms of nutritional path of supplementation. AHSCT patients were randomized to either EN or PN and were followed at baseline, 15 and 30 days posttransplant. Age, body mass index, SGA, length of stay (LOS), medical complications, severity of complications, infections, overall survival (Day 100), albumin, random blood glucose, and C‐reactive protein were evaluated. Descriptive statistics, Spearman's, chi square, correlations, and uni‐ and multivariate by type of feed, using SPSS v 29. Thirty‐six patients with complete medical and laboratory data were followed. No significance in any of the medical or nutritional parameters between the two groups was found. No correlations between SGA at any time point and type of feeding were identified. No relationship between SGA, LOS, complications, albumin, CRP, or random blood glucose at all three time points was seen. EN is a safe, convenient, and cost‐effective option for AHSCT patients since medical and nutritional outcomes were similar between those receiving EN compared to PN.


Mechanism of action of rilzabrutinib. Rilzabrutinib, a selective and reversible Bruton tyrosine kinase (BTK) inhibitor, modulates immune responses through two key mechanisms. (Left panel) In B cells, Rilzabrutinib inhibits BTK activation downstream of the B‐cell receptor (BCR), thereby reducing anti‐platelet autoantibody production. (Right panel) In macrophages, Rilzabrutinib blocks Fcγ receptor (FcγR)‐mediated signaling by preventing BTK activation, thereby inhibiting the phagocytosis of antibody‐coated platelets. Unlike irreversible BTK inhibitors, Rilzabrutinib binds non‐covalently to BTK, preserving platelet function and reducing off‐target effects.
Rilzabrutinib for the Treatment of Immune Thrombocytopenia

Advancements in the understanding of ITP pathogenesis have led to significant improvements in disease management through the use of both traditional immunosuppressive strategies and novel targeted therapies. However, a subset of patients remains refractory to treatment or achieves only transient benefits, underscoring the need for alternative therapeutic approaches. Bruton's tyrosine kinase (BTK) inhibitors have emerged as a promising strategy for autoimmune cytopenias, including ITP, due to their ability to modulate key immune pathways. Rilzabrutinib, an oral, reversible BTK inhibitor, represents a novel therapeutic approach for ITP. Rilzabrutinib, an oral, reversible BTK inhibitor, offers a novel mechanism of action by preserving platelet aggregation while reducing macrophage‐mediated platelet clearance, distinguishing it from irreversible BTK inhibitors. This review provides an updated and comprehensive analysis of the Phase 1/2 LUNA 2 trial and its long‐term extension, contextualizing rilzabrutinib within the broader treatment landscape. We also offer a comparative assessment of other BTK inhibitors investigated for ITP and discuss rilzabrutinib's potential positioning relative to existing therapies, including thrombopoietin receptor agonists (TPO‐RAs), rituximab, fostamatinib, and immunosuppressants. Results from the phase 1/2 LUNA 2 trial and its long‐term extension demonstrated that Rilzabrutinib induced a durable platelet response in 40% of patients, with a median time to response of 11.5 days. The treatment exhibited a favorable safety profile, with predominantly grade 1 or 2 adverse events and no significant safety concerns commonly associated with BTK inhibitors, such as increased bleeding risk, hepatic toxicity, or cardiac arrhythmias. Preliminary data presented at ASH 2024 from the ongoing Phase 3 LUNA 3 trial, a randomized, double‐blind study, further support rilzabrutinib's efficacy and long‐term safety. If confirmed, these findings suggest that rilzabrutinib could represent a valuable therapeutic option for patients with refractory ITP, addressing a critical unmet need and potentially redefining treatment paradigms.


Course of treatment for patient new on daratumumab (A) and ongoing on daratumumab (B).
Administered doses. There was no significant difference in the proportion of treatments that were administered as planned at the hospital or at patients' own home/at a local healthcare clinic (Fishers exact test; p values > 0.05).
Time spent on treatment administrations and reasons for unplanned contacts to the healthcare system after treatment. Time spent by patients (A) includes time spent on transportation to the healthcare clinic and to the hospital. Time spent by nurses (B) is the total time spent by hematological and primary care nurses. It includes both time spent on direct contact with the patients and time spent on administrative tasks. Horizontal lines indicate mean value; statistical significance is marked with *(p < 0.05), unpaired t‐test. Reasons for unplanned contacts to the healthcare system after a treatment at the hospital (C) and after treatment at home or at a healthcare clinic (D). There was no statistically significant difference between number of unplanned contacts after a hospital administration and an administration at home or at a healthcare clinic (Fishers exact test; p values > 0.05).
Evaluation of treatment at home/at healthcare clinics. The majority of patients were satisfied receiving treatment at home or at healthcare clinics, and 84% would like to continue this after the study.
Home‐Based Daratumumab in Patients With Multiple Myeloma

March 2025

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14 Reads

Objective Multiple myeloma is an incurable cancer with lifelong treatment needs. This, together with a global nursing shortage, calls for new approaches for future treatment. In this study, we therefore investigated the feasibility of home‐based subcutaneous daratumumab administered by primary care nurses outside the hospital. Methods Applying a mixed‐methods prospective design, we included 30 patients; 18 had completed ≥ 6 cycles of daratumumab treatment, and 12 were newly started. New patients were followed for six 28‐day cycles, with every second treatment administered outside the hospital. Patients already on treatment were followed for seven cycles with 2/3 treatments administered outside the hospital. Results Of 123 administrations planned at the hospital, 122 (97.6%) were administered and three were cancelled. Of 144 administrations planned outside the hospital, 133 (92.4%) were administered, six were redirected to the hospital, and five were cancelled. No significant difference between numbers of cancellations/redirections was observed. Patients spent significantly longer time on treatment at the hospital, even when deducting travel time. Reducing patients' visits to the hospital did not cause additional unplanned contacts with the healthcare system. Conclusion This study thus concludes that administration of daratumumab outside the hospital is safe, feasible, and time saving. Trial Registration: ClinicalTrials.gov ID: NCT05306587


Dual Targeting of Pim and PI3 Kinases in Mature T‐Cell Lymphoma

March 2025

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40 Reads

Provirus Integration site for Moloney leukemia virus (Pim) family members are well‐known oncogenes, with an expression that is restricted to few cell types including hematopoietic cells in adult organisms, making it a promising target for lymphoma treatment. Indeed, previous studies in mature T‐cell lymphoma (mTCL) cells revealed frequent upregulation of Pim expression. Nevertheless, inhibition of Pim kinases showed only minor effects on the viability of mTCL cells so far. Thus, we here addressed cellular responses to therapeutic inhibition of Pim kinases and identified a PI3K/Akt‐driven activation of mTOR as a significant escape mechanism mitigating the anti‐lymphoma effects of Pim inhibition. Indeed, dual inhibition of Pim and PI3 kinases showed synergistic anti‐lymphoma effects in vitro through downregulation of mTOR‐induced protein translation and mitigation of BCL‐xL‐mediated anti‐apoptotic mechanisms. Based on this finding, we next explored the therapeutic potential of the dual Pim/PI3K inhibitor IBL‐202 in mTCL cell lines. Strikingly, IBL‐202 strongly induced cell‐cycle‐dependent cell death in cell lines of different mTCL subtypes. Together, our study provides mechanistic evidence supporting a therapeutic strategy of dual Pim‐ and PI3‐kinase inhibition in mature T‐cell lymphoma.


Journal metrics


2.3 (2023)

Journal Impact Factor™


21%

Acceptance rate


5.5 (2023)

CiteScore™


3 days

Submission to first decision


0.996 (2023)

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$4,650.00 / £3,070.00 / €3,920.00

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