REVIEW HEMATOLOGY

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

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)

Sickle cell disease: A neglected haemoglobinopathy disorder with a huge global burden

SUMMARY

There are more than 1000 genetically determined variants of haemoglobin (Hb). Although most are harmless, some can have detrimental effect. Sickle cell disease (SCD) is the most common heritable genetic disease in the world, which affects not just the patients’ health, but also the psychological well-being of their loved ones. The SCD mutation occurs in the beta-globin gene of an adult Hb resulting in a sickle shaped Hb (HbS) which has a poor solubility and can easily polymerize during deoxygenation, leading to haemolysis and vaso-occlusion, the main hallmarks of the disease. These hallmarks are associated with both acute and chronic complications. Despite the advancement in the medical care of individuals with SCD, patients are experiencing substantial chronic dysfunctions, nevertheless several, especially genetic, modifying factors modulate patients’ outcome. This review explores the genetic basis, epidemiology, global burden, pathophysiology, complications, modifiers, and management of sickle cell disease.

(BELG J HEMATOL 2023;14(2):41–58)

How is BeQuinT supporting the Belgian hospitals to improve quality in transfusion practice and implement patient blood management?

SUMMARY

The Belgian health authorities created Belgian Quality in Transfusion (BeQuinT) in 2011 to gather experts to improve the quality of transfusion practices in Belgian hospitals. Its mission is also optimising care for patients who might need transfusion through implementation of Patient Blood Management (PBM). Its policy is based on creating and improving financial incentives, developing data-driven and IT-based tools, and providing education and guidance. In this way, BeQuinT attempts to overcome the challenges faced by clinicians and transfusion committees in implementing PBM. In clinical haematology, one of the additional challenges is the need for an individual transfusion approach taking into account the patient’s quality of life and practical aspects of care for chronically transfused patients. In this paper, an overview is presented of the past activities of BeQuinT and PBM implementation challenges followed by a brief focus on PBM in haematology.

(BELG J HEMATOL 2022;13(7):263–8)

Primary vitreoretinal lymphoma: Single centre experience and review of literature

SUMMARY

BACKGROUND: Primary vitreoretinal lymphoma (PVRL) is a rare and difficult to diagnose lymphoma. The goal of this retrospective monocentric study was to obtain clinical characteristics, to evaluate median time to diagnosis, different treatment modalities and survival outcomes.

METHODS: PVRL cases were selected from the database of the University Hospitals Leuven (Belgium) from 1^st January 2012 until 1^st January 2021. A review of the available literature was performed.

RESULTS: We included eleven cases of PVRL with a median age of 76 years (Interquartile range (IQR): 68–81). Median time to diagnosis was seven months (Range: 3–16). Presenting symptoms were blurred vision (n=11, 100%) and floaters (n=3, 27%). Bilateral eye involvement was seen in 42% (n=5). Diagnosis was made by vitrectomy and immunocytochemistry in all cases. Histopathological diagnosis was diffuse large B-cell lymphoma in all cases. Flow cytometry was used in 55% (n=6) of patients to confirm diagnosis. Initial treatment included local therapy in all patients. A combination of local and systemic therapy was given to three patients (27%). Seven patients (64%) were diagnosed with CNS relapse. No systemic relapse was seen. Median progression-free survival (PFS) and overall survival (OS) were ten (IQR: 6–32) and 26 months (IQR: 12–37). Median PFS of patients treated with local versus combined therapy was 9.7 and 18 months, respectively. However, OS of patients with local versus combination therapy was 29 and 19 months, respectively.

CONCLUSION: We analysed the clinical characteristics of eleven patients with PVRL in our hospital. The majority of these cases will eventually progress to CNS lymphoma. We saw a prolonged PFS for patients treated with combination therapy in first-line, compared to local therapy alone. However, OS was longer in patients treated with local therapy only. Despite the small cohort, these results are comparable to previous literature. Based on larger retrospective studies we conclude that local therapy as first line treatment in PVRL results in similar OS rates with less systemic toxicity compared to combination therapy.

(BELG J HEMATOL 2022;13(6):228–235)

Detecting venous thromboembolism in COVID-19 patients: DUS & CT scanning

SUMMARY

COVID-19 is associated with pulmonary thromboembolism and deep venous thrombosis. Its prevalence increases in the intensive care unit and is especially high in patients on extracorporeal membrane oxygenation (ECMO). This literature review aimed to assess the usefulness of screening for peripheral venous thrombosis or pulmonary thrombosis in patients admitted with COVID-19. In the non-ICU setting, increased D-dimer levels from baseline indicate the need for Doppler ultrasound scan of the lower limbs. In the ICU setting, clinical features and D-dimer levels may not accurately reflect the occurrence of pulmonary thromboembolism. Therefore, it is necessary to increase vigilance for VTE, with a low threshold for Doppler ultrasound and CTPA in high-risk in-patient cohorts.

(BELG J HEMATOL 2022;13(4):145–8)

Implementing cellular therapies in mantle cell lymphoma

SUMMARY

The last decade has seen much needed progress in the development of novel therapies against Mantle cell lymphoma (MCL). The licensing of the Bruton’s tyrosine kinase inhibitor (BTKi) Ibrutinib for relapsed/refractory MCL was a significant therapeutic milestone in the management of this condition and represents a highly effective, novel oral therapy in a disease characterised by progressive development of chemo-resistance. However, patients invariably progress on Ibrutinib. Multiple studies have demonstrated limited efficacy of subsequent therapies and poor outcomes post-Ibrutinib. In addition, patients with MCL displaying high-risk features such as blastoid morphology and/or TP53 mutations, are now widely recognised as a subset that are particularly challenging to manage. Brexucabtagene-autoleucel (Brexu-Cel) is a novel chimeric antigen receptor (CAR) T-cell therapy that was recently approved for management of patients relapsing on Ibrutinib. This approval was based on the ZUMA-2 study, which demonstrated impressive activity of Brexu-Cel in relapsed/refractory MCL, including in patients with high-risk features. Brexu-Cel is however not without toxicity and is associated with a moderate incidence of severe cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Importantly these adverse events are both manageable and acceptable for a therapy that holds the promise of providing long-term remissions from MCL. This review examines CAR-T therapy in MCL including the implementation of Brexu-Cel therapy in the routine management of MCL, and discusses some of the other novel cellular therapy approaches currently being evaluated in this disease.

(BELG J HEMATOL 2022;13(3):108–115)

FLT3 mutation in AML, which test for which patients?

SUMMARY

Genetic analysis of acute myeloid leukaemia (AML) has identified multiple genetic markers of prognostic significance that can be used for risk stratification of patients at diagnosis. Of these, mutations of the FMS-like tyrosine kinase 3 receptor gene (FLT3) are one of the most important. FLT3 mutations are found in 30% of AML cases overall. They are present in different AML entities and across the cytogenetic subgroups, the most common being in AML patients with a normal karyotype. They are generally considered poor prognostic indicators although the prognostic impact is influenced by the type of FLT3 mutation as well as the co-existence of other mutations and cytogenetic background. FLT3 encodes a tyrosine kinase receptor that can be targeted by tyrosine kinase inhibitors and their introduction into treatment protocols has significantly improved the prognosis of these patients with a prior dismal outcome. Given the poor prognosis, and availability of targeted treatment, FLT3 testing is recommended for all new AML cases at diagnosis with the results available within 72 hours for determination of treatment strategies. This short turnaround time (TAT) is challenging for diagnostic laboratories and affects the method of testing. Herein, we review the current recommendations for FLT3 testing in AML, discuss the different available methods for FLT3 mutation testing, and highlight considerations for AML clinicians when faced with AML patients at diagnosis or at a relapsing stage.

(BELG J HEMATOL 2022;13(2):59–64)