M. Hofmans MD, PhD

VEXAS-syndrome: A state of the art

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)

Myeloid lineage switching as escape mechanism to chimeric antigen receptor T-cell therapy in precursor B-ALL with ZNF384-TCF3 fusion: A case report

SUMMARY

Acute leukaemia with ZNF384-TCF3 fusion is considered high risk in contemporary frontline treatment protocols and will be treated by Hematopoietic Stem Cell Transplantation (HSCT) or Chimeric Antigen Receptor T-cell (CART) treatment in first complete remission. Although current cytogenetic and molecular work-up of newly diagnosed paediatric acute lymphoblastic leukaemia (ALL) includes the identification of the TCF3-ZNF384 fusion, this case underscores the importance of including this information in the choice of bridging therapy and the timing of CART treatment, as the high cytokine levels during high grade Cytokine Release Syndrome (CRS) might drive ALL cells to lineage switching.

(BELG J HEMATOL 2022;13(3):128–32)

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)

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)

PP01 Exploring the long non-coding RNA landscape in Juvenile Myelomonocytic Leukemia

P09 A case of chronic eosinophilic leukemia with secondary transformation to acute myeloid leukemia