T. Lammens PhD

Precision medicine in relapsed and refractory paediatric haematological malignancies and the role of an International Tumour Board

SUMMARY

Despite improvements in the outcome of newly diagnosed paediatric haematological malignancies, the prognosis of refractory and high-risk relapsed patients remains poor, and their treatment is challenging. The increased use of molecular and functional profiling technologies and the growing number of targeted therapies provide opportunities to alter the treatment landscape of these patients and offer the potential to improve patient outcomes. However, this approach comes with many challenges. First, there is a need for accessibility to the analysis and interpretation of sequencing technologies. Second, the prioritisation of targetable events and matching treatments needs to be established. Third, there is a need to facilitate access to early-phase clinical trials. Recently, the international Leukaemia/Lymphoma Target Board (iLTB, NCT05270096, ITCC107) was initiated by the Prinses Máxima Centre and developed in collaboration with the international community to address these barriers. The iLTB provides a forum for an international panel of experts to advise the treating physicians on the best possible treatment options for their patients diagnosed with relapsed or refractory haematological malignancies, for which there is no standard treatment option. In addition, the iLTB aims to facilitate enrolment in clinical trials and collect structured real-world data on patients treated with compassionate use programs. The purpose of this article is to discuss the current challenges in relapsed and refractory haematological malignancies and to introduce the use of international tumour boards to help physicians when confronted with difficult cases.

(BELG J HEMATOL 2024;15(7):263–8)

Practice guidelines for the therapeutic drug monitoring of asparaginase in acute lymphoblastic leukaemia

SUMMARY

Asparaginase is an essential therapeutic in the treatment of acute lymphoblastic leukaemia (ALL) in children and adults. Currently, there are three asparaginase products in clinical use: native Escherichia coli asparaginase, Erwinia chrysanthemi asparaginase and PEG-asparaginase. One of the important side effects is the occurrence of hypersensitivity reactions, such as clinical allergy or silent inactivation that can lead to inactivation of asparaginase with a negative impact on the outcome of the patient. Therapeutic drug monitoring (TDM) has proven to be a valuable tool to monitor asparaginase activity and detect decreased or absent activity at an early stage. Therefore, many contemporary paediatric ALL protocols include TDM of asparaginase as standard of care. In this report, the background of asparaginase hypersensitivity and silent inactivation is described and a practical flowchart regarding the use and TDM of PEG- and Erwinia asparaginase for patients with ALL is introduced.

(BELG J HEMATOL 2022;13(6):236–42)

Current developments and hurdles in CAR-T cell therapy for acute myeloid leukaemia

SUMMARY

Despite huge progress in the past decades, the overall survival (OS) of patients with acute myeloid leukaemia (AML) remains poor. The treatment options run low for those refractory or intolerant to first and second line treatment or in case of relapse. The need for alternative treatment is great and imperative to further improve the OS of these patients. The success of CAR-T19 therapy for the treatment of B cell acute lymphoblastic leukaemia has demonstrated the feasibility of delivering these therapies, and success in further improving survival rates. Among others, the fundamental biological factor limiting the applicability of CAR-T immuno-therapy in the treatment of AML includes the lack of a leukaemia-specific antigen, or an antigen shared by leukaemia blasts and haematopoietic stem and progenitor cells whose sustained depletion could be clinically tolerated. In this review, we describe the most recent developments, clinical results and challenges in CAR-T cell therapy for AML.

(BELG J HEMATOL 2021;12(6):244-50)

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)

Retrospective analysis of the incidence and characteristics of paediatric myelodysplastic syndrome and juvenile myelomonocytic leukaemia in Belgium

SUMMARY

Childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukaemia (JMML) are very rare clonal stem cell disorders of early childhood. Paediatric MDS can be further subdivided in refractory cytopenia of childhood (RCC) and high grade MDS, in case of excess blasts. Given their rarity, little is known about the epidemiology of these diseases in Belgium. The aim of this study is to investigate the incidence, characteristics, treatment and prognosis of paediatric MDS and JMML in Belgium. Prospectively collected data of 56 Belgian patients with MDS and JMML were enrolled in the study, of which 41 (73%) with MDS, eleven with JMML (20%) and four (7%) with Noonan syndrome associated myeloproliferative disorder. The incidence rates of MDS and JMML in Belgium were 1.5 and 0.4 per million children per year respectively, with a median age of diagnosis of 9.3 years for RCC, 9.5 years for high grade MDS and 2.6 years for JMML. Monosomy 7 was the most common cytogenetic abnormality and could particularly be found in high grade MDS (33%) and JMML (45%). RCC treatment consisted of immunosuppressive therapy (IST) and haematopoietic stem cell transplantation (HSCT), but in high grade MDS and JMML only HSCT was a valid treatment option. Overall survival was significantly lower in high grade MDS (45.0%) compared to JMML (79.5%) and RCC (80.6%) (log-rank p-value = 0.038), whereas event-free survival (EFS) was comparably low in high grade MDS and JMML (46.7% and 58.4% respectively) due to a high cumulative incidence of relapse (CIR) of 33% and 29.9%, respectively. Outcome was best for RCC patients with highest EFS (76.3%; 57.1% if IST failure was considered as event) and lowest CIR (9.3%). This study highlights that paediatric MDS and JMML are very rare disorders with associated morbidity and mortality, especially in high grade MDS and JMML. Considering the high relapse risk in high grade MDS and JMML, new therapeutic options are required.

(BELG J HEMATOL 2020;11(6):233-9)

Leukaemic stem cells in AML: where are we now? An update on recent findings and detection

SUMMARY

Ample evidence was provided these past decades that leukaemic stem cells (LSC) play a role in the outcome of adult and paediatric acute myeloid leukaemia (AML) patients. Although it is generally accepted that the CD34+/ CD38- compartment is most LSC-enriched, novel data have emerged illustrating a distinct biology between CD34+ and CD34- AML. In this review, we discuss the main LSC phenotypes in CD34+ and CD34- AML , as they are of utmost importance for the development of broadly applicable LSC-targeted strategies. The leukaemia-initiating capacity of these cells upon xenografting is still considered to be the gold standard for LSC detection. However, more feasible techniques have been researched to allow the implementation of LSC measurements into clinical practice. Here, we summarise the current state-of-the-art methodologies using flow cytometry and molecular detection, and emphasise their relevance in terms of prognosis and targeted drug therapy.

(BELG J HEMATOL 2020;11(6):246-52)

Recent advances in the genomic and epigenomic biology of juvenile myelomonocytic leukaemia

SUMMARY

Juvenile myelomonocytic leukaemia is a heterogeneous disease caused by constitutional activation of the Ras signal transduction pathway. The clinical course of the disease is variable and non-specific. In the majority of patients prompt hematopoietic stem cell transplantation is necessary for long-term survival, whereas in a minority the disease will resolve without treatment. In more than 90% of the patients, mutations in one or more of the following genes can be found (somatic NRAS, KRAS and PTPN11, germline NF1 and CBL). However, these canonical mutations are insufficient to explain the phenotypic heterogeneity of this disease. More recently, secondary mutations, non-coding RNA expression, and genomic DNA methylation have led to a better understanding of the pathobiology of the disease, and shown to play a role in the classification and prognostication of this rare disease. In addition, this novel information has been crucial for novel drug development and introduction of novel patient-tailored therapies, which are currently being tested in vitro or in vivo in clinical trials.
(BELG J HEMATOL 2020;11(2):49–55)