HEMATOTHESIS

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)

Oncogenic co-operation in T-cell acute lymphoblastic leukaemia: The role of TLX3 and TCF7::SPI1

SUMMARY

T-cell acute lymphoblastic leukaemia (T-ALL) is a devastating disease, which mainly occurs in childhood. Despite an improvement of the overall survival, the current treatments have many side effects, and patients with relapsed or refractory disease continue to have a very poor prognosis. T-ALL arises from T-cell progenitors that have acquired multiple genomic lesions, which co-operate to drive leukaemia development. For some genetic alterations, such as the TCF7::SPI1 fusion or ectopic expression of TLX3, their role in driving leukaemia remains largely unknown. Therefore, we first investigated the co-operation between TCF7::SPI1 and NRAS(G12D). Using a mouse model, we were able to show that β-catenin is a crucial coactivator for the oncogenic function of the TCF7::SPI1 fusion protein. In the second part, we demonstrated that TLX3 and FLT3-ITD co-operate in driving leukaemia by activating the SPI1/PU.¹ transcriptional program in an ex vivo pro-T-cell model and mouse model. This oncogenic function of TLX3 was shown to be dependent on other cofactors. Together, these two models of oncogenic co-operation in T-ALL demonstrate that the interaction between oncogenic transcription factors and cofactors is paramount for their function. Thus, these data provide a rationale for developing treatments directed at these protein interactions in the future for leukaemia.

(BELG J HEMATOL 2022;13(8):325–7)

Novel therapeutic targets in juvenile myelomonocytic leukaemia: Are noncoding RNAs valuable treatment options?

SUMMARY

Juvenile myelomonocytic leukaemia is a rare and aggressive clonal disease of early childhood for which hematopoietic stem cell transplantation remains the only curative option, albeit with a high relapse rate and many associated toxicities. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have recently been implicated in a variety of biological processes, including haematopoiesis and receive much research attention as they possess features interesting for treatment, such as tissue specificity, low overall expression and easy targetability with RNAi or gene editing technology. Within this dissertation, we aimed at deciphering the lncRNA and circRNA transcriptome of JMML and use this knowledge to develop novel treatments.

(BELG J HEMATOL 2021;12(4):173-6)

Faster to the fungus: rapid diagnostic and prognostic tests for invasive fungal diseases

SUMMARY

Invasive mould infections such as invasive aspergillosis or mucormycosis remain an important infectious complication in haematology patients, especially in those undergoing intensive chemotherapy for acute myeloid leukaemia or undergoing allogeneic stem cell transplantation. An early diagnosis and timely initiation of antifungal therapy improves outcomes. In this thesis, we therefore looked at new possible diagnostic tools to aid in a rapid diagnosis, such as lateral flow assays, PCR tests, or a novel beta-D-glucan assay. Furthermore, we explored how we could get the maximum out of existing tests such as galactomannan, by optimising their use after therapy in an effort to assess the response to therapy.

(BELG J HEMATOL 2020;12(3):138-40)

Non-substitutive strategies to improve haemophilia care in developing countries: Experience in Côte d’Ivoire

SUMMARY

In developing countries, the high rate of haemophilia-related mortality and morbidity is mainly caused by a lack of knowledge, underdiagnoses and very limited access to treatment. This work carried out in Côte d’Ivoire as a part of the World Federation of Hemophilia twinning program, aimed to evaluate the impact of non-substitutive strategies (not based on concentrates of coagulation factors) on the management of haemophilia. This project sought at developing and validating education materials to improve knowledge on haemophilia, implementing a self-physiotherapy program, and obtaining cross-cultural and validated tools to assess the quality of life of people with haemophilia. These initiatives were the starting point for haemophilia care in Côte d’Ivoire, by providing patients with low-cost measures and creating an environment favourable for the use of substitutive treatment issued from humanitarian aid. This thesis was defended at UCLouvain on September 01, 2020. The full manuscript of this these is available on dial.uclouvain.be.

(BELG J HEMATOL 2020;12(2):90-2)

A multicentric observational study on the management of hyperleukocytic acute myeloid leukaemia in Belgium

SUMMARY

INTRODUCTION

In hyperleukocytic acute myeloid leukaemia (AML) the risk of leukostasis is high due to the rapid increase in WBC count and the size of the myeloid blasts. It is associated with poor prognosis due to an increased risk of early death and relapse. Immediate initiation of cytoreductive treatment is essential to improve outcome, but evidence to prefer hydroxyurea, leukapheresis, intensive chemotherapy (IC) or a combination treatment, is lacking. Therefore, we decided to investigate the current approach of hyperleukocytic AML in Belgium.

METHODS

A brief questionnaire on the management of hyperleukocytic AML was sent to all Belgian centres currently treating AML with IC and was replied by ten centres. Four centres agreed to a more detailed retrospective analysis. All newly diagnosed AML patients presenting with hyperleukocytosis between January 2013 and April 2019 were included. Patient and disease characteristics were collected, as well as treatment choice and outcome parameters.

RESULTS

We included 121 patients with a median WBC count of 116,360/µL. Mortality at day 21 was 20% and overall mortality was 64% at a median follow-up of six months. Twenty percent received leukapheresis, which was started within 24 hours. There was no difference in age distribution, treatment intensity or time to start IC between patients receiving leukapheresis or not. Although the leukapheresis group had a more severe presentation with a higher median WBC and blast count and a worse performance status, there was no difference in response to therapy, early or long-term mortality. In a multivariate analysis, age at diagnosis and treatment modality (IC vs non-IC) were the only independent parameters that significantly affected early death.

CONCLUSION

Evidence on optimal treatment options in hyperleukocytic AML is lacking. We could not demonstrate any added value of leukapheresis. To improve the prognosis of this dramatic presentation, national or even European databases should be used to document and learn from the outcome of current practice.

(BELG J HEMATOL 2020;11(7):325-34)