REVIEW HEMATOLOGY

FLT3 inhibitors after allogeneic haematopoietic stem cell transplantation in paediatric AML

BJH - volume 14, issue 8, december 2023

A.S. van Velzen MD, PhD, B.F. Goemans MD, PhD, A.B. Versluys MD, PhD

SUMMARY

In 15–20% of children with acute myeloid leukaemia (AML), a mutation in the FMS-like tyrosine kinase 3 (FLT3) protein is present. This is usually an internal tandem duplication (FLT3-ITD), an activating mutation that ensures cell survival and proliferation. A FLT3-ITD mutation is associated with a lower chance of survival and is an indication for allogeneic stem cell transplantation (SCT) in children with AML. Since the risk of relapse after allogeneic SCT can be up to 40%, additional treatment after allogeneic SCT is also being investigated. In recent decades, several targeted therapies have been developed for patients with AML, including several generations of FLT3 inhibitors (tyrosine kinase inhibitors). The effect of these inhibitors has already been demonstrated in adult patients with AML; however, the role of FLT3 inhibitors in children with AML with an FLT3-ITD mutation is not yet fully understood. In this article, we discuss the role of FLT3 inhibitors after allogeneic stem cell transplantation for children with AML.

(BELG J HEMATOL 2023;14(8):331–5)

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Gene therapy for von Willebrand Disease

BJH - volume 14, issue 8, december 2023

S. Vandelanotte MSc, B. Calcoen MD, C. Tersteeg PhD, K. VanHoorelbeke PhD, S.F. De Meyer PhD

SUMMARY

von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by mutations in the von Willebrand factor (VWF) gene. These mutations can affect the biosynthesis, secretion, function or clearance of VWF. As a result, quantitative or qualitative abnormalities of VWF lead to the bleeding phenotype found in VWD patients. Current management of VWD aims at correcting the bleeding phenotype via the use of supportive therapy, stimulating the release of endogenous VWF reserves and implementation of replacement strategies. Despite current treatment options, VWD patients experience a substantial negative impact on their overall health-related quality-of-life (HRQoL). Development of long-term approaches to manage VWD would not only avoid the current limitations of short-term therapies but could also significantly ameliorate the HRQoL of VWD patients. Gene therapy for VWD offers the potential of a long-term, if not lifelong, correction of VWF deficiency. During the last two decades, gene therapy for VWD has been studied via different strategies. The aim of this review is to give an overview of the different strategies and improvements that were investigated to develop a gene therapy for VWD.

(BELG J HEMATOL 2023;14(8):326–30)

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The impact of drone transport on blood quality

BJH - volume 14, issue 7, november 2023

J. Van Bael MSc, N. Callewaert Apr, C. Tersteeg PhD

SUMMARY

Drone transport is employed in several countries to deliver blood products to remote locations difficult to access by cars. Additionally, it offers a swift and secure way of transporting blood tubes from collection sites to laboratories for subsequent analysis. However, during drone transport the blood is exposed to vibrations, g-forces and variable ambient temperatures. Ensuring the preservation of the quality of blood samples during aerial transportation is a crucial prerequisite for the widespread utilisation of drones for blood transportation. In this review, we will summarise the current knowledge on the impact of drone transport on hematological and biochemical parameters.

(BELG J HEMATOL 2023;14(7):274–7)

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Rethinking the reimbursement of innovative medicines in oncology: Looking beyond overall survival

BJH - volume 14, issue 6, october 2023

M. Piccart MD, PhD, J. Vansteenkiste MD, PhD, H. Prenen MD, PhD, F. Duhoux MD, PhD, A. Janssens MD, PhD, M. Delforge MD, PhD, A. Awada MD, PhD, P. Neven MD, PhD, A. Sibille MD, B. Neyns MD, PhD

SUMMARY

The oncological treatment landscape is evolving at a very rapid pace with a continuous stream of novel treatment options. To fully leverage these therapeutic advances in clinical practice it is important to facilitate a rapid access to innovative anticancer drugs for patients. Specifically for Belgium, the delay from EMA approval to reimbursement for anticancer drugs is very long, with an average of almost 600 days, and a substantial proportion of innovative drugs never make it to the patient. The stringent focus of the Belgian Commission for Reimbursement of Medicines (CRM) on overall survival (OS) data in reimbursement decisions is believed to be an important contributor to this situation. However, the ever-increasing pace at which new anticancer therapies are being developed in combination with an earlier detection of cancer will make it increasingly difficult to present mature OS data at the time of regulatory approval in the years to come. As such, there is an urgent need for a debate with the regulators to consider more readily available endpoints in their reimbursement assessments. In fact, when a strong treatment effect is seen on an intermediate endpoint such as disease-free or progression-free survival, a benefit in OS is quite likely. As such, our reimbursement system needs to be adapted to better align with the scientific progress in oncology. In this, a temporary reimbursement decision based on intermediate endpoints could give Belgian patients earlier access to promising lifesaving medicines. In this, we as oncologists, including specialists in haematology, respiratory oncology, and gastrointestinal cancer, strongly encourage the CRM to use the grading provided by the ESMO magnitude of clinical benefit scale to evaluate the clinical added value of future cancer treatments. This will not only facilitate a faster patient access to innovative therapies, but will also help policy-makers in advancing ‘accountability for reasonableness’ in their resource allocation deliberations.

(BELG J HEMATOL 2023;14(6):245–9)

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VEXAS-syndrome: A state of the art

BJH - volume 14, issue 6, october 2023

G. Stevens MD, R. Callens MD, M. Hofmans MD, PhD, T. Kerre MD, PhD

SUMMARY

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an acquired, late-onset disorder, almost exclusively described in male patients. This new clinical entity is associated with autoinflammation and haematological abnormalities, such as Myelodysplastic Syndrome, Monoclonal Gammopathy of Undetermined Significance (MGUS) and Multiple Myeloma (MM). Common laboratory abnormalities are chronic inflammation, macrocytic anaemia, thrombocytopenia and lymphopenia. The diagnosis is genotype-based by the identification of myeloid-restricted somatic mutations in the UBA1 gene, exclusively found on the X-chromosome. A bone marrow aspirate and trephine biopsy are crucial in the diagnostic work-up, demonstrating the typical finding of vacuoles. Clear scientific support comparing different treatment strategies in VEXAS syndrome is still lacking. Currently, corticosteroid treatment remains the cornerstone in the control of inflammatory flare-ups. Corticosteroid-sparing regimens such as methotrexate, tumour necrosis factor inhibitors, anti-interleukine-6, and anti-interleukine-1 agents have only been able to demonstrate a short-term response. While an allogeneic haematopoietic stem cell transplantation (allo-HSCT) seems to be the only long-lasting curative treatment to eradicate the causing pathogenic UBA1 clones, ideal candidate selection and timing for allo-HSCT remain unclear. Recently, some case reports have demonstrated promising results when integrating the use of hypomethylating agents or ruxolitinib in the treatment of patients with VEXAS syndrome. As VEXAS syndrome remains a fatal disease with a mean 5-year mortality of up to 40%, clinicians should be aware of its existence, clinical work-up and possible treatment strategies.

(BELG J HEMATOL 2023;14(6):236–44)

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Targeting the immune system in MDS and MPN: Understanding the immunome and responses to immunotherapy – Part 2

BJH - volume 14, issue 4, june 2023

G. Maggioni MD, A. Poloni MD, PhD, M.G. Della Porta MD, S. Kordasti MD, PhD

SUMMARY

In the first part of these reviews, we highlighted the intricate nature of the immune response in myelodysplastic neoplasms (MDS) and myeloproliferative neoplasms (MPN). It has been demonstrated that inflammation and immune cellular response may vary significantly at different stages of the diseases. Consequently, patients may present with a broad range of symptoms, from auto-inflammation to autoimmunity. Despite considerable progress in comprehending the role of immune dysregulation in MDS and MPN, immunotherapy strategies have thus far had only a marginal effect on these diseases. Nevertheless, several novel immunomodulatory drugs are currently undergoing clinical trials, which may change our clinical practice. In this part, we provide an overview of current clinical trials and the necessary strategies to better stratify patients for these innovative immunomodulatory treatments.

(BELG J HEMATOL 2023;14(4):155–69)

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Immune dysregulation in MDS and MPN: An immunological mess – Part 1

BJH - volume 14, issue 3, may 2023

G. Maggioni MD, M.G. Della Porta MD, S. Kordasti MD, PhD

SUMMARY

In recent decades, immune dysregulation has emerged as a leading factor in the pathogenesis of myelodysplastic neoplasms (MDS) and myeloproliferative neoplasms (MPN), in addition to somatic mutations. Beyond commonly used immunotherapies (e.g., haematopoietic stem cell transplantation, immunosuppressive therapy, interferon-alpha and lenalidomide), many strategies targeting the immune system are currently under evaluation, such as increasing tumour cell elimination via T cells targeting antigens with cell-mediated inhibition or costimulatory signals, stimulating macrophage-mediated tumour elimination, or reducing immunosuppression driven by myeloid-derived suppressor cells. Interesting results were obtained with drugs targeting the crosstalk between tumour cells and macrophages and the immune checkpoint inhibitors, particularly when combined with hypomethylating agents. However, this approach is not convincing overall and is unlikely to change clinical practice in the near future. One reason is related to a non-classic tumour microenvironment in “liquid” haematologic malignancies, which, unlike in solid tumours, has easier accessibility to the most immunogenic malignant clones with subsequent elimination by immune cells. Furthermore, immune system dysregulation is highly heterogeneous within the same type of disease both because it is influenced by somatic mutation type and the grade of inflammation and because it dynamically changes during disease progression. Therefore, the most effective approach to immune therapy is to characterise each patient’s disease thoroughly. This can be done by integrating information about the mutational status, the type and grade of immune system disruption, and the other extrinsic players in disease pathogenesis like the microbiome, inflammation, and bone marrow niche. A comprehensive and multifactorial ‘immune-scoring’ system will result in more robust patient stratification and will help to identify the most suitable immunotherapy for each patient.

(BELG J HEMATOL 2023;14(3):105–13)

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