REVIEW HEMATOLOGY

Advancements in thrombophilia testing: The role of multi-gene panels in venous thromboembolism

SUMMARY

Venous thromboembolism (VTE) is a prevalent condition with a significant acute and long-term morbidity and results from a complex interaction between genetic and environmental risk factors. About half of VTE cases are unprovoked, suggesting an underlying thrombophilia. Nevertheless, conventional thrombophilia tests, which assess deficiencies in antithrombin, protein C, and protein S, and the presence of the prothrombotic factor V Leiden and prothrombin G20210A variants, identify an underlying inherited predisposition in about 40% of VTE cases. These tests lack specificity for VTE and mostly fail to guide therapeutic decisions. Over the past decade, multi-gene panels utilising high-throughput sequencing have been developed to rapidly analyse a preselected set of VTE-risk genes of which most are involved in (anti)coagulation. Initial studies show that these panels can identify variants missed by conventional testing in approximately 40% of both patients with positive and negative thrombophilia workups. However, only about 10% of VTE patients carry previously undetected (likely) pathogenic variants that are of immediate relevance for counselling. The high prevalence of variants of uncertain significance (VUS) and oligogenic variants complicate data interpretation. Further research is necessary to characterise and reclassify these VUS and to evaluate the therapeutic implications of multi-gene panel testing.

(BELG J HEMATOL 2025;16(4):146–51)

The role of UBTF-TD mutations in paediatric acute myeloid leukaemia and myelodysplastic syndrome

SUMMARY

Paediatric acute myeloid leukaemia (pAML) and myelodysplastic syndrome (pMDS) are rare yet clinically significant haematologic malignancies, associated with poor prognosis. Recent studies have identified upstream binding transcription factor tandem duplications (UBTF-TD) as a potential novel genetic driver lesion in leukaemogenesis. UBTF encodes a nucleolar protein involved in ribosomal RNA transcription and chromatin remodelling. UBTF-TD pAML and pMDS is characterised by aberrant recruitment to HOXA/B clusters, leading to a leukaemic gene expression profile. Moreover, UBTF-TD is frequently associated with FLT3-ITD, WT1 and RAS-pathway mutations. Given its distinct molecular profile and prognostic significance, UBTF-TD is increasingly recognised as a novel subclass-defining lesion in paediatric myeloid malignancies. Further research is required to identify effective therapeutic interventions to improve patient outcomes, but Menin-inhibitors show promising results. This review consolidates current knowledge on UBTF-TD mutations, covering their molecular landscape, clinical implications and potential therapeutic considerations.

(BELG J HEMATOL 2025;16(4):152–9)

Desensitisation as treatment option in patients with drug hypersensitivity

SUMMARY

Allergic reactions to drugs are a common problem. Desensitisation is a procedure in which temporary tolerance can be achieved to medication that previously induced hypersensitivity reactions. Successful desensitisation with chemotherapeutic agents and biologicals can ensure that patients can continue to receive the first-choice therapy. This review first examines the background of hypersensitivity reactions and desensitisation therapy. Subsequently, cases are described with different types of hypersensitivity reactions followed by subsequent successful desensitisation treatments.

(BELG J HEMATOL 2025;16(4):160–8)

Prime-time for lncRNA signatures in acute myeloid leukaemia?

SUMMARY

Long non-coding RNA (lncRNA) signatures have emerged as important prognostic biomarkers in acute myeloid leukaemia (AML), stratifying patients into high-risk and low-risk groups and thus providing valuable insights for personalised treatment strategies. The development of these signatures often involves comprehensive bioinformatics analyses, employing various statistical methods to ensure robustness and accuracy. Nevertheless, many reports are flawed by the presence of specific biases and/or incompleteness. Here we performed a comprehensive review of recently identified prognostic lncRNA signatures in AML, including our own report on a 69-lncRNA signature predicting relapse-free survival in paediatric acute myeloid leukaemia. Next to their predictive impact, we provide insights into their strengths and shortcomings.

(BELG J HEMATOL 2025;16(2):54–64)

Restoring the delicate coagulation balance in haemophilia

SUMMARY

Thrombophilia is very prevalent in the general population. In patients with haemophilia, it leads to an attenuation of their bleeding phenotype. Rebalancing agents work in similar fashion by targeting the natural anticoagulants, which enhances thrombin generation, and restores the balance of coagulation. The most important targets are antithrombin, tissue factor pathway inhibitor (TFPI) and activated protein C with its cofactor protein S. Antithrombin levels can be lowered by the short interfering RNA fitusiran via subcutaneous injection, which results in more thrombin generation and clot formation. Its efficacy was demonstrated in patients with haemophilia A and B, with and without inhibitors. The other clinically advanced drugs are concizumab and marstacimab, which both inhibit TFPI, thereby relieving the suppression of the extrinsic pathway, and reducing the bleeding rate in patients with haemophilia. Initially, several thrombotic events were observed in patients using fitusiran and concizumab, but these could be managed by using an adapted dosing strategy. Finally, several compounds target either activated protein C or protein S. The development of SerpinPC, inhibiting protein C, was recently halted, but other drugs continue to be under clinical development and show promising results. In short, rebalancing agents are effective in selected patients with haemophilia, and they could potentially even open new possibilities to treat many hitherto neglected rare bleeding disorders.

(BELG J HEMATOL 2025;16(3):111–7)

Non-myeloablative haploidentical haematopoietic stem cell transplantation for adult patients with sickle cell disease: Current status and future perspectives

SUMMARY

Allogeneic haematopoietic stem cell transplantation is a curative therapy for patients with sickle cell disease. The introduction of non-myeloablative conditioning regimens has made this treatment accessible to adult patients with sickle cell disease. Due to the limited availability of HLA-identical related donors and poor outcomes of matched unrelated donor transplantations, research of the past years has focused on developing new conditioning regimens to improve the outcomes of haploidentical transplantations. This overview article discusses the findings of a recently published phase II study on non-myeloablative haploidentical haematopoietic stem cell transplantation in patients with sickle cell disease. Additionally, the article discusses the effects of transplantation on sickle cell disease-related complications and future perspectives.

(BELG J HEMATOL 2025;16(3):118–24)

Approach to febrile neutropenia in Belgian hospitals

SUMMARY

Background: Febrile neutropenia (FN) is an important complication in high-risk haematological patients, occurring in 80–90% of cases. While rapid initiation of broad-spectrum antibiotics has improved FN-related mortality, the optimal duration of treatment remains controversial. Prolonged use of antibiotics not only leads to resistance and toxicity but also to increased mortality and GVHD in allogeneic stem cell transplantation recipients due to disruption of the microbiome. Different guidelines provide different recommendations, leading to inconsistent practice and the ECIL guidelines are not widely implemented.

Methods: A national survey was conducted in Belgium to assess current practices for the management of FN in high-risk haematological patients. The electronic survey, consisting of 40 questions, was distributed to haematology centres via the newsletter of the Belgian Society of Haematology in January 2023. Responses from seventeen large haematology centres, including university hospitals, were analysed.

Results: Prophylactic measures such as germ-free diets and fluoroquinolone use were common, with 13/17 centres implementing germ-free diets and 11/17 centres using fluoroquinolone prophylaxis. Empirical broad-spectrum antibiotic treatment (EBAT) was initiated as monotherapy in 15/17 centres, predominantly with piperacillin-tazobactam (8/17) or third-/fourth-generation cephalosporins (7/17). Escalation to broader-spectrum antibiotics was common when FN persisted, with 9/17 centres using this approach. De-escalation practices varied, with 12/17 centres de-escalating if the patient showed improvement despite a severe initial presentation. Withdrawal of EBAT before neutrophil recovery occurred in 15/17 centres in stable, afebrile patients.

Discussion: The survey revealed partial compliance with the ECIL guidelines, with variations in escalation and de-escalation practices. While most centres followed recommended empirical treatments, de-escalation and early cessation remain difficult. The findings highlight the need for further research to optimise antibiotic use, reduce associated risks and reduce healthcare costs.

Conclusions: Although Belgian centres show better adherence to ECIL guidelines compared to other regions, challenges remain in de-escalation and early cessation of EBAT. A multicentre randomised controlled trial is needed to establish the safety of shorter EBAT durations and to improve antimicrobial stewardship.

(BELG J HEMATOL 2024;15(8):307–12)