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The Lancet. Haematology Mar 2024Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute...
Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study.
BACKGROUND
Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia.
METHODS
We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1-5 and venetoclax (variable doses of 100-400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with ClinicalTrials.gov, NCT04655755, and is currently enrolling participants.
FINDINGS
Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27-94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3-4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6-16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation.
INTERPRETATION
This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data.
FUNDING
MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech/AbbVie, and Astex Pharmaceuticals.
Topics: Humans; Male; Female; Adult; Middle Aged; Aged; Aged, 80 and over; Decitabine; Treatment Outcome; Leukemia, Myelomonocytic, Chronic; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Sulfonamides; Uridine; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 38316133
DOI: 10.1016/S2352-3026(23)00367-8 -
Proceedings of the National Academy of... Sep 2023Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the...
Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of . Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout () and the conditional myelomonocytic-lineage HMGB1-knockout () mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that , whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of . Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings, mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.
Topics: Animals; Mice; Mesothelioma, Malignant; Tumor Necrosis Factor-alpha; HMGB1 Protein; Mesothelioma; Asbestos; Inflammation; Tumor Microenvironment
PubMed: 37729199
DOI: 10.1073/pnas.2307999120 -
Cancers Dec 2023Myeloid neoplasms and acute leukemias include different entities that have been recently re-classified taking into account molecular and clinicopathological features.... (Review)
Review
Myeloid neoplasms and acute leukemias include different entities that have been recently re-classified taking into account molecular and clinicopathological features. The myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) category comprises a heterogeneous group of hybrid neoplastic myeloid diseases characterized by the co-occurrence of clinical and pathological features of both myelodysplastic and myeloproliferative neoplasms. The most frequent entity in this category is chronic myelomonocytic leukemia (CMML) which is, after acute myeloid leukemia (AML), the main myeloid disorder prone to develop cutaneous manifestations. Skin lesions associated with myelodysplastic and myeloproliferative neoplasms include a broad clinical, histopathological and molecular spectrum of lesions, poorly understood and without a clear-cut classification in the current medical literature. The aim of this review is to describe and classify the main clinical, histopathological and molecular patterns of cutaneous lesions in the setting of MDS/MPN in order to improve the diagnostic skills of the dermatologists, hematologists and pathologists who deal with these patients.
PubMed: 38136431
DOI: 10.3390/cancers15245888 -
Haematologica Dec 2023Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a...
Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss of function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells (HPCs) also demonstrated sensitivity of SH2B3- mutated HPCs to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.
PubMed: 38152053
DOI: 10.3324/haematol.2023.283776 -
Frontiers in Immunology 2023Classically, particle-induced periprosthetic osteolysis at the implant-bone interface has explained the aseptic loosening of joint replacement. This response is preceded... (Review)
Review
Classically, particle-induced periprosthetic osteolysis at the implant-bone interface has explained the aseptic loosening of joint replacement. This response is preceded by triggering both the innate and acquired immune response with subsequent activation of osteoclasts, the bone-resorbing cells. Although particle-induced periprosthetic osteolysis has been considered a foreign body chronic inflammation mediated by myelomonocytic-derived cells, current reports describe wide heterogeneous inflammatory cells infiltrating the periprosthetic tissues. This review aims to discuss the role of those non-myelomonocytic cells in periprosthetic tissues exposed to wear particles by showing original data. Specifically, we discuss the role of T cells (CD3, CD4, and CD8) and B cells (CD20) coexisting with CD68/TRAP multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants.
Topics: Humans; Osteolysis; Joint Prosthesis; Osteoclasts; Inflammation; Polyethylene
PubMed: 38106424
DOI: 10.3389/fimmu.2023.1310262 -
Expert Review of Hematology 2023The diagnosis of myelodysplastic syndrome (MDS) is complex. Flow cytometric analysis of the myelomonocytic compartment can be helpful, but it is highly subjective and... (Review)
Review
INTRODUCTION
The diagnosis of myelodysplastic syndrome (MDS) is complex. Flow cytometric analysis of the myelomonocytic compartment can be helpful, but it is highly subjective and reproducibility by non-specialized groups is unclear. Analysis of the erythroid lineage by flow cytometry is emerging as potentially more reproducible and easier to conduct, while keeping a high diagnostic performance.
AREAS COVERED
We review the evidence in this area, including 1) the use of well-established markers - CD71 and CD36 - and other less well-established markers and parameters; 2) the use of flow cytometric scores for the erythroid lineage; and 3) additional aspects, including the emergence of computational tools and the roles of flow cytometry beyond diagnosis. Finally, we discuss the limitations with the current evidence, including 1) the impact of the sample processing protocol and reagents on the results, 2) the lack of a standard gating strategy, and 3) conceptualization and design issues in the available publications.
EXPERT OPINION
We end by offering our recommendations for the current use - and our personal take on the value - of the analysis of erythroid lineage by flow cytometry.
Topics: Humans; Flow Cytometry; Reproducibility of Results; Myelodysplastic Syndromes; Immunophenotyping
PubMed: 38018383
DOI: 10.1080/17474086.2023.2289534 -
Cancers Nov 2023Leukemia cutis (LC) is defined as the leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously... (Review)
Review
Leukemia cutis (LC) is defined as the leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously with the diagnosis of systemic leukemia. However, cutaneous lesions are occasionally diagnosed as the primary manifestation of leukemia. Leukemic skin infiltrations demonstrate considerable variation regarding a number of changes, distribution, and morphology. The highest incidence of LC is observed in chronic lymphocytic leukemia, monocytic and myelomonocytic acute myeloid leukemia, and T-cell lineage leukemia. Although the pathogenic mechanism of the invasion of leukemic cells into the skin is not well understood, chemokine receptors and adhesion molecules as well as the genetic characteristics of leukemia are thought to play a role. Leukemic skin lesions may be localized or disseminated and may occur alone or in combination on any site of the skin, most frequently in the trunk and extremities. The most common clinical presentations of leukemia cutis are papules, nodules, macules, plaques, and ulcers. In most patients, the complete or partial resolution of cutaneous infiltrations occurs simultaneously with hematologic remission. However, in patients with resistant disease or recurrent skin infiltration, local radiotherapy can be used. This review presents recent data on the pathogenesis, diagnosis, and treatment of leukemic skin involvement in different types of leukemia.
PubMed: 38001655
DOI: 10.3390/cancers15225393 -
Microbes and Infection 2023PRRSV is capable of evading the effective immune response, thus persisting in piglets and throughout the swine herd. We show here that PRRSV invades the thymus and...
PRRSV is capable of evading the effective immune response, thus persisting in piglets and throughout the swine herd. We show here that PRRSV invades the thymus and causes depletion of T-cell precursors and alteration of the TCR repertoire. Developing thymocytes are affected during negative selection when they transit from the triple-negative to triple-positive stages at the corticomedullary junction just before entering the medulla. The restriction of repertoire diversification occurs in both helper and cytotoxic αβ-T cells. As a result, critical viral epitopes are tolerated, and infection becomes chronic. However, not all viral epitopes are tolerated. Infected piglets develop antibodies capable of recognizing PRRSV, but these are not virus neutralizing. Further analysis showed that the lack of an effective immune response against the critical viral structures results in the absence of a germinal center response, overactivation of T and B cells in the periphery, robust production of useless antibodies of all isotypes, and the inability to eliminate the virus. Overall, the results show how a respiratory virus that primarily infects and destroys myelomonocytic cells has evolved strategies to disrupt the immune system. These mechanisms may be a prototype for how other viruses can similarly modulate the host immune system.
Topics: Swine; Animals; Porcine respiratory and reproductive syndrome virus; Porcine Reproductive and Respiratory Syndrome; Antibodies, Viral; Epitopes; B-Lymphocytes
PubMed: 37142116
DOI: 10.1016/j.micinf.2023.105146 -
Bulletin of Experimental Biology and... Jan 2024Obesity is associated with chronic persistent inflammation due to a pool of tissue macrophages that can penetrate the blood-brain barrier and cause neuroinflammation....
Obesity is associated with chronic persistent inflammation due to a pool of tissue macrophages that can penetrate the blood-brain barrier and cause neuroinflammation. The analysis of the association of CD14CD163 monocytes in the peripheral blood with cognitive functions in 56 obese children (mean age 11.95 (9.45; 14.45) years) was carried out. The control group consisted of 10 children (mean age 10.4 (9.3; 13.8) years). Standard deviation of the body mass index (SDS BMI) and height (SDS height) were calculated using WHO AnthroPlus software (for children of 6-19 years). Body composition was assessed using bioimpedance measurement. Mononuclear cells were isolated from whole blood by centrifugation on a Ficoll-Urografin density gradient (ρ=1.077 g/ml). The content of CD14CD163 monocytes in the peripheral blood was assessed by flow cytometry. To analyze cognitive functions, the intelligence coefficient (IQ) was calculated and a Russian adaptation of the Rey test was performed. We found an increase in the number of M2-polarized CD14CD163 monocytes in the peripheral blood with an increase in the obesity degree and in the presence of cognitive decline, as well as a negative correlation of the level of M2-polarized monocytes and IQ, taking into account the excess of visceral fat. The revealed data on the relationship of M2-polarized CD14CD163 peripheral blood monocytes with obesity in children and the development of neuropsychological deficiency confirm the role of peripheral visceral obesity and neuroinflammation.
Topics: Humans; Child; Pediatric Obesity; Neuroinflammatory Diseases; Monocytes; Antigens, Differentiation, Myelomonocytic; Flow Cytometry; Inflammation
PubMed: 38340199
DOI: 10.1007/s10517-024-06029-8 -
Acta Neuropathologica Communications May 2024Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to...
BACKGROUND
Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology.
METHODS
The morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis.
RESULTS
Morphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases.
CONCLUSIONS
In conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.
Topics: Humans; Lewy Body Disease; Alzheimer Disease; Female; Male; Aged; Aged, 80 and over; Neuroinflammatory Diseases; Microglia; Astrocytes; alpha-Synuclein; tau Proteins; Antigens, CD; Amyloid beta-Peptides; Middle Aged; Antigens, Differentiation, Myelomonocytic; Brain; CD68 Molecule
PubMed: 38715119
DOI: 10.1186/s40478-024-01786-z