HEMATOTHESIS

Circulating cell-free DNA: A novel pathway to the genome of Hodgkin lymphoma

SUMMARY

The low abundance of Hodgkin/Reed-Sternberg (HRS) cells in lymph node biopsies in classical Hodgkin lymphoma (cHL) complicates the analysis of somatic genetic alterations in HRS cells. As circulating cell-free DNA (cfDNA) contains circulating tumour DNA (ctDNA) from HRS cells, we prospectively collected cfDNA from 177 patients with newly diagnosed, mostly early-stage cHL in a monocentric study at Leuven, Belgium (n=59) and the multicentric BREACH study by Lymphoma Study Association (n=118). To catalogue the patterns and frequencies of genomic copy number aberrations (CNAs), cfDNA was sequenced at low coverage (0.26×), and data were analysed with ichorCNA to yield read depth-based copy number profiles and estimated clonal fractions in cfDNA. At diagnosis, the cfDNA concentration, estimated clonal fraction, and ctDNA concentration were significantly higher in cHL cases than controls. More than 90% of patients exhibited CNAs in cfDNA. The most frequent gains encompassed 2p16 (69%), 5p14 (50%), 12q13 (50%), 9p24 (50%), 5q (44%), 17q (43%), 2q (41%). Losses mostly affected 13q (57%), 6q25–q27 (55%), 4q35 (50%), 11q23 (44%), 8p21 (43%). In addition, we identified loss of 3p13–p26 and of 12q21–q24 and gain of 15q21–q26 as novel recurrent CNAs in cHL. At diagnosis, ctDNA concentration was associated with advanced disease, male sex, extensive nodal disease, elevated erythrocyte sedimentation rate, metabolic tumour volume, and HRS cell burden. CNAs and ctDNA rapidly diminished upon treatment initiation, and persistence of CNAs was associated with increased probability of relapse. This study endorses the development of ctDNA as gateway to the HRS genome and substrate for early disease response evaluation.

(BELG J HEMATOL 2023;14(4):183–5)

Outpatient management of patients with acute myeloid leukaemia during intensive consolidation chemotherapy: A feasibility study

SUMMARY

Introduction: Fit patients with acute myeloid leukaemia (AML) are treated with intensive therapy. This consists of an induction (intensive chemotherapy) and a consolidation (intensive chemotherapy and/or stem cell transplantation). Because of the risk of complications during these different cycles, patients are followed up in-hospital in most Belgian centres. However, the consolidation course is considered tolerable and could possibly be followed up on an outpatient basis, which may also have a financial and psychological benefit.

Objective: To identify patients for whom an outpatient approach is medically justified. To this end, prognostic factors predicting the development of neutropenic fever, intensive care unit (ICU) admission and chemotherapy-related mortality (day 30 mortality) were investigated.

Methods: Retrospective analysis of all patients aged sixteen years and older with a new diagnosis of AML who underwent at least one consolidation course at the Ghent University Hospital during the period February 2016 to November 2020.

Results: One hundred and fifty-five cycles of consolidation chemotherapy were listed in 83 patients. The average duration of hospitalisation was 22.4 days. At least one episode of neutropenic fever occurred in 52 courses (33.5%). The occurrence of neutropenic fever in the previous cycle of chemotherapy was significantly associated with a higher risk of developing neutropenic fever in the subsequent cycle (p = 0.04). In a multivariate analysis, this parameters were associated with neutropenic fever with an odds ratio of 1.9 (0.90–4.01) (p = 0.09). Given the rare occurrence of an ICU admission (n = 3) and early mortality (n = 1), it was not meaningful to perform statistical analysis on this.

Conclusion: Outpatient follow-up of a consolidation chemotherapy cycle for AML is feasible. Prospective follow-up research is needed to confirm this and to investigate the economical and psychological impact.

(BELG J HEMATOL 2023;14(3):139–44)

Anaemia and its association with asymptomatic malaria, iron and zinc deficiencies, and Ferroportin Q248H mutation in children aged under five years in South Kivu, Democratic Republic of Congo

SUMMARY

Anaemia is a public health problem affecting one quarter of the global population with significant health consequences as well as an adverse impact on social and economic development. In malaria endemic areas, Plasmodium infection remains the major cause of anaemia. The ferroportin Q248H mutation has been described to protect red blood cells against oxidative stress and malaria infection. The objective of this study was to describe the main mechanisms causing anaemia and the role of ferroportin Q248H mutation in relation with anaemia and malaria in childhood in a Bantu population living in the volcanic region of South Kivu. 1088 healthy children aged under five years were randomly selected in the health zone of Miti Murhesa in South Kivu/Democratic Republic of Congo. Almost 40% of children under five years were anaemic, submicroscopic Plasmodium infection was as high as 22.3%. The prevalence of ferroportin Q248H mutation was 11.4%. No difference was observed in the frequencies of malaria or anaemia between ferroportin mutated compared to ferroportin wild type children. The prevalence of iron deficiency was found to be high (49.1%) when free erythrocyte protoporphyrin (FEP) was used to assess iron status. We found zinc deficiency in 17.6% of children. The prevalence of anaemia in South Kivu remains high, children with low parasitemia detected by loop mediated-isothermal amplification assay (LAMP) but not by microscopy showed a significantly increased prevalence of anaemia. Ferritin, an acute phase protein of infection is less suited to assess iron status in endemic areas of Plasmodium infection.

(BELG J HEMATOL 2022;13(7):281–3)

Genetic drivers of peripheral T-cell lymphomagenesis

SUMMARY

Peripheral T-cell lymphomas represent an unmet medical need. The paucity of biological studies impedes the development of new treatment strategies. In this doctoral thesis, I leveraged next-generation sequencing technologies to identify new gene fusions in peripheral T-cell lymphomas. These insights were used to engineer cell systems and mouse models, which closely resemble human peripheral T-cell lymphomas. These models are valuable tools to understand the biology of peripheral T-cell lymphomas and provide a rational for new treatment regimens.

(BELG J HEMATOL 2022;13(6):253–5)

TCR-based T cell immunotherapy for AML: Multidimensional aids in optimising treatment and patient identification

SUMMARY

Acute myeloid leukaemia (AML) has a dismal outcome, as demonstrated by a 5-year overall survival rate of only 26%. Although a complete remission can be achieved in approximately 50% of the patients with classical chemotherapy, the chances of relapse are high. Current treatment options for relapsed or refractory AML only offer a bridge to allogeneic haematopoietic stem cell transplantation since no other curative option exists. In primary refractory patients, and patients at high risk for relapse, harnessing the power of the immune system with immunotherapy might provide a new treatment option. In this dissertation, we approached AML immunotherapy from two sides: the optimisation of TCR-based immunotherapy for AML, and of the identification of patients eligible for this type of treatment.

(BELG J HEMATOL 2022;13(4):165–7)

Risk factors, diagnosis and management of (azole-resistant) invasive aspergillosis

INTRODUCTION

An invasive fungal disease (IFD) is a life-threatening infection that is almost exclusively diagnosed in immunocompromised hosts. The most common invasive mould infection is caused by Aspergillus species and called invasive aspergillosis (IA). Patients with acute myeloid leukaemia who are treated with intensive chemotherapy and hematopoietic stem cell transplant recipients are at highest risk for IA. Incidence rates of IA vary substantially and depend on host and environmental factors but also the modalities of allogeneic stem cell transplantation recipients as well as the use of antifungal prophylaxis. Without prophylaxis the incidence of IA in these populations can be as high as 10–20%.^1–3 IA does not only lead to a higher overall mortality and morbidity but also to substantially higher medical costs.⁴ The case fatality rate of IA is estimated to lie between 20–38%, six to twelve weeks after diagnosis but this as well varies substantially between populations.⁵ Therefore, optimising the management of IA is key in order to reduce the burden of this devastating complication in the immunocompromised host. For more than fifteen years voriconazole, a drug of the triazole class, has been the recommended treatment for this life-threatening infection after a pivotal randomised trial showed an improved survival with voriconazole compared with amphotericin B deoxycholate. However, also with voriconazole and improved diagnostic tests, the overall 6-week mortality is still unacceptably high at 25–30%.⁶ A troublesome emerging problem in patients with IA is the increasing incidence of infections with triazole-resistant A. fumigatus. Although limited by numbers, case series have demonstrated that the overall mortality of patients infected with triazole-resistant A. fumigatus is very high (50–88%).^7,8 This thesis focuses on risk factors for and the diagnosis of invasive aspergillosis. Additionally, the management of azole-resistant aspergillosis is addressed. The thesis consisted of several chapters. You can read all chapters in the digital version of the thesis. We briefly summarise the most important findings in every chapter.

(BELG J HEMATOL 2021;12(8):353–4)

Immunity, the Epstein-Barr virus and the microenvironment in lymphoma

SUMMARY

Immune regulation therapy or ‘immunotherapy’ has been a major evolution in the field of cancer therapy in the last decade. The goal of this thesis was to better characterise multiple rare lymphoproliferative disorders in order to guide therapy development, predictive biomarker discovery and ultimately help ensuring that these novel therapies can get to the patients who stand to benefit from them. Many lymphoma types arise in a context of altered immune system function with potential implications for immunotherapy. One example of lymphoma arising in the context of chronic immune stimulation is Helico bacter Pylori infection, which is known as mucosa associated lymphoid tissue (MALT) lymphoma of the stomach. For this lymphoma we reviewed the literature and described how it is an excellent model to understand lymphomas arising in an immune stimulated context.¹ Other lymphomas arise in a context of immunosuppression, of which post-transplant lymphoproliferative disorders (PTLD) are the best characterised. Besides the immune state, the presence of a virus such as the Epstein-Barr virus has major effects on lymphomas and their (immune) microenvironment with potential impact on immunotherapy. A review of EBV-related effects on PTLDs was done.² Lymphoproliferative disorder’s (LPDs) arising in the context of treatment with immunomodulatory (IM)/immunosuppressive (IS) drugs for various auto-immune diseases are lesser-known. These are called immunomodulation related lymphoproliferative disorders (IARLPD). For this thesis, we characterised one of the largest single centre case series of IARLPD.³ Finally, some lymphomas arise in specific ‘immune-privileged’ sites such as the central nervous system (CNS) called Primary central nervous system lymphoma (PCSNL). Digital slide analysis method and the novel MILAN multiplex staining technique were used to study the tumour microenvironment (TME) in PCNSL confirming the relevance of the microenvironment in the clinical behaviour of this lymphomas, highlighting potential relevance of immunotherapy and confirming the usefulness of the mentioned techniques in the study of the TME.⁴ For the purpose of this dissertation presentation we will focus primarily on this latter work.

(BELG J HEMATOL 2021;12(6):280-2)