The clinical spectrum and biological findings in RAS-associated juvenile myelomonocytic leukemia and RAS-associated autoimmune leukoproliferative disorder

Introduction: Juvenile myelomonocytic leukemia (JMML) and RAS-associated lymphoproliferative disease (RALD) are both hematologic diseases with related gene mutations, such as KRAS or NRAS. In addition, most of the RALD patients fulfill the diagnostic criteria of JMML making it a real challenge to discriminate between both diseases. However, the prognosis of JMML patients is generally poor, whereas the long-term follow-up of patients with RALD suggests a more indolent course. The objective of this study was to establish clinical and biological hallmarks that could differentiate JMML from RALD in patients with KRAS and NRAS mutations, to optimize patient care. Methodology: We conducted a systematic review with data about the clinical and biological characteristics collected from case reports and cohort studies describing patients diagnosed with KRAS- or NRAS-mutated JMML or RALD. Statistical analyses were performed with SPSS. To assess the differences between patients diagnosed with JMML and patients diagnosed with RALD, the Chi-Square test, and Fisher’s Exact test were used to compare qualitative variables. To compare quantitative variables, an Independent two-sample t-test and Mann-Whitney U test were used. Results: Comparing the categorical variables, significant differences in the gender distribution, the presence of an abnormal karyotype, monocytosis, and granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity were noted between both patient groups. When comparing the blood cell counts, a higher white blood cell (WBC) count, monocyte count, lymphocyte count, and percentage of circulating blasts in peripheral blood (PB) were reported in the JMML group. When comparing KRAS-mutated JMML and KRAS-mutated RALD, differences in the gender distribution, the presence of an abnormal karyotype, and age at diagnosis/onset were observed. When comparing the blood cell counts, a higher WBC count and monocyte count were found in the JMML group. When comparing NRAS-mutated JMML and NRAS-mutated RALD, a difference in the distribution of splenomegaly was seen, together with the higher WBC count in the JMML group. Interestingly, a diagnosis of RALD is more likely if autoimmune manifestations are present. Conclusion: With this study, we found a clear overlap between both diseases, although some differences could be noted. Given this overlap, JMML and RALD may be two extremities of the same disease spectrum rather than two distinct entities

Retrospective study of children with chronic myeloid leukemia treated in Belgium between 2000 and 2021

Introduction: Chronic myeloid leukemia (CML) in children and adolescents is a rare disease with an annual incidence of one case per million. The condition is characterized by the translocation t(9;22)(q34;q11.2) resulting in a BCR-ABL1 fusion oncoprotein localized on the newly formed Philadelphia (Ph) chromosome. With the current retrospective study, we aimed to identify the clinical and biological characteristics of Belgian CML patients up to 18 years treated in Belgium between 2000 and 2021, as well as to evaluate the response to treatment, potential long-term side effects, and prognosis. Methodology: Children and adolescents up to 18 years of age treated for CML in eight Belgian pediatric hemato-oncology centers between 2000 and 2021 were included in the present study as part of an international registry study (I-CML-Ped Study). The data of the pediatric CML patients were collected in a Belgian CML registry on case report forms (CRFs) after which they were inserted into a database. IBM SPSS Statistics was used for statistical analysis of the data. Survival curves were made using the Kaplan-Meier method. Results: A total of 30 pediatric CML patients treated between 2000 and 2021 in Belgium were included for data analysis. The population consisted of 10 boys and 20 girls with a mean age of 9 years (range 1-16 years). The mean follow-up time was 99 months with a range of 8 to 247 months. The first symptoms of CML were from most to least common: asthenia, weight loss, abdominal pain, fever, and bleeding. The spleen was palpable in 22 patients with a mean of 10 cm below the costal margin (range 1-20 cm). Twenty-nine patients were in the chronic phase (CML-CP) at diagnosis, while one patient was in the blast phase (CML-BC). In the pre-TKI era (before 2004), the majority of the patients were treated with an HSCT preceded by Hydrea. After 2004, the standard first treatment was imatinib. The overall survival (OS) of all included patients was 96.7%. Conclusion: In general, the clinical and biological characteristics of the Belgian pediatric CML population are in line with the literature. Although the outcome is excellent, it is essential to consider the long-term side effects of TKI treatment and a hematopoietic stem cell transplantation (HSCT) and weigh the advantages and disadvantages of both treatments

CAR-T in the Treatment of Acute Myeloid Leukemia: Barriers and How to Overcome Them

Conventional therapies for acute myeloid leukemia (AML) are characterized by high rates of relapse, severe toxicities, and poor overall survival rates. Thus, the development of new therapeutic strategies is crucial for improving the survival and quality of life of AML patients. CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy has been extremely successful in the treatment of B-cell acute lymphoid leukemia and several mature B-cell lymphomas. However, the use of CAR T-cell therapy for AML is currently prevented due to the lack of a myeloid equivalent to CD19, as currently known cell surface targets on leukemic blasts are also expressed on healthy hematopoietic stem and progenitor cells as well as their progeny. In addition, the immunosuppressive tumor microenvironment has a dampening effect on the antitumor activity of CAR-T cells. Here, we review the therapeutic challenges limiting the use of CAR T-cell therapy for AML and discuss promising novel strategies to overcome them

DECIPHERING THE NON-CODING RNA LANDSCAPE OF PEDIATRIC ACUTE MYELOID LEUKEMIA

DECIPHERING THE NON-CODING RNA LANDSCAPE OF PEDIATRIC ACUTE MYELOID LEUKEMI