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Frontiers in Immunology 2023Burkitt lymphoma (BL) is the most common tumor of non-Hodgkin's lymphoma (NHL) in children, accounting for about 40% of cases. Although different combined short-course...
Case Report: Unedited allogeneic chimeric antigen receptor T cell bridging to conditioning-free hematopoietic stem cell transplantation for a child with refractory Burkitt lymphoma.
PURPOSE
Burkitt lymphoma (BL) is the most common tumor of non-Hodgkin's lymphoma (NHL) in children, accounting for about 40% of cases. Although different combined short-course chemotherapies have achieved a good effect, refractory/relapsed BL has a poor prognosis with cure rates less than 30%. Chimeric antigen receptor T cell (CAR-T) therapy has developed rapidly in recent years and achieved excellent results in acute lymphoblastic leukemia (ALL). However, in some cases, there is a failure to produce autologous CAR-T cells because of T-cell dysfunction. In such cases, allogeneic CAR-T therapy has to be considered.
METHODS
A 17-year-old boy with stage II BL did not respond to extensive chemotherapy and sequential autologous CAR-T therapy. Lentiviral vectors containing anti-CD20-BB-ζ (20CAR) and anti-CD22-BB-ζ (22CAR) transgenes were used to modify the T cells from an HLA-identical matched unrelated donor. Flow cytometry was used to assess the cytokine analyses and CAR-T cell persistence in peripheral blood, enumerated by qPCR as copies per ug DNA. Informed consent for autologous/allogeneic CAR-T therapy was obtained from the patient and his legal guardian.
RESULTS
Unedited HLA-matched allogeneic CD20 and CD22 CAR-T cells were infused after lymphodepletion chemotherapy with cyclophosphamide and fludarabine. The patient experienced Grade IV cytokine release syndrome (CRS) and went into complete remission (CR) after anti-inflammatory treatment including tocilizumab. Because of persistent pancytopenia and full donor chimerism, the same donor's conditioning-free peripheral blood stem cells were successfully transplanted 55 days post CAR-T. Neutrophils were engrafted at day +11 and platelets were rebuilt at day +47 without obvious acute graft-versus-host disease (GVHD), but there was mild chronic GVHD in the skin and eyes. Currently, active anti-rejection therapy is still underway.
CONCLUSION
Unedited HLA-matched allogeneic CAR-T cell therapy could be an innovative, effective, and safe treatment for children with refractory/relapse BL without obvious acute GVHD. Conditioning-free allogeneic hematopoietic stem cell transplantation (HSCT) from the same donor is feasible for a patient with full donor T-cell chimerism after allogeneic CAR-T. It cannot be ignored that close GVHD monitoring is needed post HSCT.
Topics: Male; Humans; Child; Adolescent; Receptors, Chimeric Antigen; Burkitt Lymphoma; T-Lymphocytes; Hematopoietic Stem Cell Transplantation; Immunotherapy, Adoptive
PubMed: 37736096
DOI: 10.3389/fimmu.2023.1219872 -
Infection & Chemotherapy Dec 2023Cytopenias serve as common indicators and crucial predictive tools for evaluating disease progression and therapeutic outcomes in individuals with human immunodeficiency...
BACKGROUND
Cytopenias serve as common indicators and crucial predictive tools for evaluating disease progression and therapeutic outcomes in individuals with human immunodeficiency virus (HIV) infection. This study aimed to assess the prevalence of cytopenias and their correlation with the level of immunosuppression in treatment-naive HIV-infected participants after initiating highly active combined antiretroviral drug therapy (cART24).
MATERIALS AND METHODS
This prospective study focused on evaluating cytopenia in 44 treatment-naive HIV-infected patients who consented to initiate cART and were consecutively enrolled. The research was conducted at the Nasara HIV Treatment & Care Centre of Ahmadu Bello University Teaching Hospital (ABUTH), Zaria, Nigeria, spanning from December 2016 to January 2018. Cytopenias, including anemia, leucopenia, lymphocytopenia, and thrombocytopenia, were defined and assessed according to World Health Organization guidelines. A combination of cross-sectional and longitudinal mixed-design two-step analysis was employed to validate our findings.
RESULTS
The median time from enrollment to cART initiation was 7 days, following the universal test and treat protocol. The prevalence of cytopenia was 75% at the baseline before treatment and increased to 84% after cART24 administration. There were no statistically significant differences in the median values of immuno-hematological parameters between baseline and after cART24 initiation ( >0.05). In terms of longitudinal assessment, the prevalence of anemia, leucopenia, lymphopenia, and thrombocytopenia at baseline were 66%, 23%, 0%, and 11%, respectively, and after cART24, the rates were 66%, 29%, 5%, and 20%. Notably, the prevalence of cytopenia correlated with declining CD4+ T cell counts. Among instances of unicytopenia, 58% exhibited isolated anemia, 6% had lone leucopenia, and 6% had solitary thrombocytopenia. Additionally, 27% demonstrated bi-cytopenia, and 3% exhibited pancytopenia. Interestingly, none of the study participants presented with lymphopenia. The most common combination was anemia and thrombocytopenia. Both longitudinal and cross-sectional analytical findings were consistent.
CONCLUSION
In treatment-naive HIV-infected individuals, the prevalence of cytopenias, particularly anemia and thrombocytopenia, was substantial and correlated with the degree of immunosuppression as indicated by CD4+ T cell counts. These cytopenias persisted despite initiation of cART24, highlighting the complexity of hematological manifestations in HIV infection. Our study underscores the significant hematopathological impact of HIV and antiretroviral therapy, highlighting the necessity for preventive strategies to mitigate these adverse effects.
PubMed: 38183393
DOI: 10.3947/ic.2023.0080 -
Frontiers in Immunology 2023Idiopathic acquired aplastic anemia (AA) is considered an immune-mediated syndrome of bone marrow failure since approximately 70% of patients respond to...
Idiopathic acquired aplastic anemia (AA) is considered an immune-mediated syndrome of bone marrow failure since approximately 70% of patients respond to immunosuppressive therapy (IST) consisting of a course of anti-thymocyte globulin (ATG) followed by long-term use of ciclosporin. However, the immune response that underlies the pathogenesis of AA remains poorly understood. In this study, we applied high-dimensional mass cytometry on bone marrow aspirates of AA patients pre-ATG, AA patients post-ATG and healthy donors to decipher which immune cells may be implicated in the pathogenesis of AA. We show that the bone marrow of AA patients features an immune cell composition distinct from healthy donors, with significant differences in the myeloid, B-cell, CD4 and CD8 T-cells lineages. Specifically, we discovered that AA pre-ATG is characterized by a disease-specific immune cell network with high frequencies of CD16 myeloid cells, CCR6 B-cells, Th17-like CCR6 memory CD4 T-cells, CD45RACCR7CD38 CD8 T-cells and KLRG1 terminally differentiated effector memory (EMRA) CD8 T-cells, compatible with a state of chronic inflammation. Successful treatment with IST strongly reduced the levels of CD16 myeloid cells and showed a trend toward normalization of the frequencies of CCR6 B-cells, CCR6 memory CD4 T-cells and KLRG1EMRA CD8 T-cells. Altogether, our study provides a unique overview of the immune landscape in bone marrow in AA at a single-cell level and proposes CCR6 as a potential new therapeutic target in AA.
Topics: Humans; Anemia, Aplastic; Bone Marrow; CD8-Positive T-Lymphocytes; Cyclosporine; Pancytopenia; Antilymphocyte Serum
PubMed: 38094307
DOI: 10.3389/fimmu.2023.1274116 -
Journal, Genetic Engineering &... Nov 2023Aplastic anemia (AA) is a bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia which can lead to life-threatening complications. Our...
BACKGROUND
Aplastic anemia (AA) is a bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia which can lead to life-threatening complications. Our objective was to study the telomerase genes (TERT and TERC) variants, explore their relationship to telomere shortening and TERT gene expression, and to identify variants in the MPL gene within Egyptian AA patients.
METHODS
Forty AA patients and 40 sex- and age-matched healthy individuals as the control group were studied through sequencing of TERT, TERC, and MPL genes. Quantitative real-time PCR (qRT-PCR) was used for measuring TERT gene expression. Telomere length (TL) was measured using the Quantitative Fluorescence In Situ Hybridization (Q-FISH) technique. In silico analysis was performed for the prediction of the pathogenicity of resultant variants.
RESULTS
Sequencing of MPL, TERT, and TERC genes identified 26 variants. Eleven variants were identified in the MPL gene. Three of them are pathogenic: two missense [c.305 G>A, c.1589 C>T] and one splice site [g.9130T>G]. TERT gene sequencing showed thirteen variants, among them, four novel [c.484G>A, c.499G>A, c.512G>A, c.3164C>G] and two previously reported [c.835G>A, c.2031C>T] were predicted to be pathogenic. Two variants were characterized within the TERC gene; n.514A>G and n.463 C>T. TERT gene expression was downregulated in 70% of studied patients and the Q-FISH technique detected telomere shortening in 82.5% of patients.
CONCLUSIONS
Twenty-six pathogenic and benign variants within the TERC, TERT, and MPL genes were identified among the studied AA patients that were in several cases associated with shortened telomeres and/or lower TERT gene expression. Genotype/phenotype correlation in AA patients is of great importance in explaining the disease severity and guiding therapeutic decisions.
PubMed: 38017244
DOI: 10.1186/s43141-023-00585-8 -
Cureus Jul 2023Kaposi Sarcoma Inflammatory Cytokine Syndrome (KICS) is a serious, uncommon disease that occurs in patients who are positive for HIV and human herpesvirus-8 (HHV-8). It...
Kaposi Sarcoma Inflammatory Cytokine Syndrome (KICS) is a serious, uncommon disease that occurs in patients who are positive for HIV and human herpesvirus-8 (HHV-8). It is characterized by a constellation of clinical findings, including fever, weight loss, and fluid retention, as well as a lack of multicentric Castleman disease (MCD) features on histopathology and an elevated serum HHV-8 viral load. Diagnosis is often delayed, and treatment options are limited, culminating in high mortality rates. We hereby present a 32-year-old male patient with HIV who was untreated for a few years and came with fever, night sweats, pancytopenia, and widespread adenopathy. A thorough evaluation of opportunistic infections was unremarkable. Clinically MCD was suspected, but lymph node biopsy only showed Kaposi sarcoma (KS) with no characteristic features of MCD. However, with clinical deterioration, KICS was strongly suspected. Kaposi sarcoma immune reconstitution syndrome (KS-IRIS) was also a possibility as the patient was restarted on antiretroviral therapy. Rituximab was commenced, but the patient suffered a cardiac arrest and could not be revived. Alternative diagnosis must be explored in patients with HIV presenting with constitutional symptoms, cytopenia, and adenopathy after opportunistic infections and malignancies are ruled out. If they have KS with HHV-8 positivity and there is a lack of characteristic features of MCD in lymph node biopsy, prompt suspicion of KICS should be made, and treatment with rituximab and/or chemotherapy should be instituted rapidly. KS-IRIS is also possible if patients have recently received antiretroviral therapy and have a rapid decline in viral load and increase in CD4 counts (immunological recovery). HHV8 viral load levels may help to distinguish between these two inflammatory conditions.
PubMed: 37605703
DOI: 10.7759/cureus.42218 -
World Journal of Clinical Cases Jul 2023Brucellosis is one of the most common zoonotic infectious diseases in the world, with approximately 500000 new cases of human brucellosis diagnosed each year....
BACKGROUND
Brucellosis is one of the most common zoonotic infectious diseases in the world, with approximately 500000 new cases of human brucellosis diagnosed each year. Brucellosis can simulate various multi-system diseases, presenting atypical symptoms. Very few brucellosis cases with pancytopenia accompanied by a severe hearing loss have been reported. In the literature review, we could find only one similar case reported in the past. Moreover, this disease is easily misdiagnosed as a blood system disease leading to delayed treatment. Thus, it is important to improve clinicians' awareness of this disease.
CASE SUMMARY
A 64-year-old woman presented with dizziness and fatigue, accompanied by pancytopenia and severe hearing loss. was identified on blood culture. Anti-infective therapy with rifampicin (900 mg/d) and doxycycline (100 mg twice a day) was prescribed for 4 mo along with ceftriaxone 2 g/d for 1 mo. The patient showed a good response to antibiotic therapy. Her blood counts returned to normal followed by significant improvement in hearing.
CONCLUSION
Brucellosis should be considered in the differential diagnosis of patients presenting with pancytopenia and hearing loss.
PubMed: 37583865
DOI: 10.12998/wjcc.v11.i21.5187 -
Case Reports in Rheumatology 2023Illustration of a case of systemic mastocytosis mimicking reactive arthritis in the absence of an infectious etiology.
OBJECTIVES
Illustration of a case of systemic mastocytosis mimicking reactive arthritis in the absence of an infectious etiology.
METHODS
Review of the patient's medical records.
RESULTS
We report a case of systemic mastocytosis relapse, presenting with pancytopenia accompanied by knee monoarthritis, cystitis, and bilateral conjunctivitis occurring simultaneously at the same time interval within 2-4 days, mimicking reactive arthritis in the absence of an infectious etiology.
CONCLUSION
Our case demonstrated reactive arthritis features (triad of urethritis, conjunctivitis, and arthritis) without an infectious trigger but rather a relapse of mastocytosis. We should think outside the box when faced with such a clinical scenario in the absence of an infectious etiology. Paraneoplastic reactive arthritis is to be considered after excluding an underlying infection.
PubMed: 37584057
DOI: 10.1155/2023/6655005 -
Medicine Sep 2023There is no bibliometric study in the literature on Aplastic Anemia (AA). In the present study, the purpose was to summarize the intellectual structure of the subject,...
There is no bibliometric study in the literature on Aplastic Anemia (AA). In the present study, the purpose was to summarize the intellectual structure of the subject, uncover the global productivity in this respect, and identify the latest research trends by performing a bibliometric analysis of the articles published on AA. For this purpose, outputs for different research components of scientific outputs (i.e., countries, institutions, journals, and authors) were analyzed. A total of 3221 articles on Aplastic Anemia published between 1980 and 2022 were analyzed by using various statistical methods and bibliometric approaches. The Spearman Correlation Coefficient was used for correlation analysis and bibliometric network visualization maps were used to identify trending topics, citation analysis, and international collaborations. The top 3 contributing countries to the literature were the USA in this respect (800, 24.8%), China (514, 15.9%), and Japan (442, 13.7%). The top 3 most active institutions were the National Institutes of Health USA (n = 177), National Heart Lung Blood Institute (n = 153), and Udice French Research Universities (n = 136). The top 3 most productive journals were the British Journal of Haematology (n = 239), Blood (n = 181), and Bone Marrow Transplantation (n = 137). The most prolific author was Neal Stuart Young (n = 130). Specific keywords that were most frequently used in articles were severe aplastic anemia, immunosuppressive therapy, pediatrics/children, anti-thymocyte globulin, cyclosporine, hematopoietic stem cell transplantation, myelodysplastic syndromes, Paroxysmal Nocturnal Hemoglobinuria, hepatitis-associated aplastic anemia, allogeneic stem cell transplantation, haploidentical hematopoietic stem cell transplantation, pancytopenia, eltrombopag, fludarabine, Graft-Versus-Host Disease, survival, apoptosis, cytokines, and cyclophosphamide. It was determined that the trend topics in recent years were eltrombopag, COVID-19, Treg, Th17, thrombopoietin receptor agonists, haploidentical hematopoietic stem cell transplantation, haploidentical donor/transplantation, and posttransplantation cyclophosphamide. In the formation of the AA literature, it was determined that the research leadership belonged to the USA, China, Japan, European countries (United Kingdom, Italy, Germany, France, Switzerland), India, and South Korea, which have large economies.
Topics: United States; Humans; Child; Anemia, Aplastic; COVID-19; Bibliometrics; Cyclophosphamide
PubMed: 37682205
DOI: 10.1097/MD.0000000000034862 -
Clinical Case Reports Apr 2024Care must be taken to mitigate the effect of cognitive bias in times of frequent common presentations. The etiology of bicytopenias and pancytopenias must always be...
Care must be taken to mitigate the effect of cognitive bias in times of frequent common presentations. The etiology of bicytopenias and pancytopenias must always be carefully investigated. Blast cells in low count B ALL may not be seen on a peripheral smear and diagnosis often requires confirmational bone marrow aspirate with flow cytometry and molecular typing.
PubMed: 38659496
DOI: 10.1002/ccr3.8800 -
Experimental Hematology Jun 2024SAMD9 and SAMD9L are two interferon-regulated genes located adjacent to each other on chromosome 7q21.2. Germline gain-of-function (GL GOF) mutations in SAMD9/SAMD9L are... (Review)
Review
SAMD9 and SAMD9L are two interferon-regulated genes located adjacent to each other on chromosome 7q21.2. Germline gain-of-function (GL GOF) mutations in SAMD9/SAMD9L are the genetic cause of MIRAGE syndrome, ataxia-pancytopenia (ATXPC) syndrome, myeloid leukemia syndrome with monosomy 7 (MLSM7), refractory cytopenia of childhood (RCC), transient monosomy 7 in children, SAMD9L-associated autoinflammatory disease (SAAD), and a proportion of inherited aplastic anemia and bone marrow failure syndromes. The myeloid neoplasms associated with GL GOF SAMD9/SAMD9L mutations have been included in the World Health Organization (WHO) 2022 classification. The discovery of SAMD9/SAMD9L-related diseases has revealed some interesting pathobiological mechanisms, such as a high rate of primary somatic compensation, with one of the mechanisms being (transient) monosomy 7 a mechanism also described as "adaption by aneuploidy." The somatic compensation in the blood can complicate the diagnosis of SAMD9/SAMD9L-related disease when relying on hematopoietic tissues for diagnosis. Recently, GL loss-of function (LOF) mutations have been identified in older individuals with myeloid malignancies in accordance with a mouse model of SAMD9L loss that develops a myelodysplastic syndrome (MDS)-like disease late in life. The discovery of SAMD9/SAMD9L-associated syndromes has resulted in a deeper understanding of the genetics and biology of diseases/syndromes that were previously oblivious and thought to be unrelated to each other. Besides giving an overview of the literature, this review wants to also provide some practical guidance for the classification of SAMD9/SAMD9L variants that is complicated by the nonrecurrent nature of these mutations but also by the fact that both GL GOF, as well as loss-of-function mutations, have been identified.
Topics: Humans; Chromosomes, Human, Pair 7; Myelodysplastic Syndromes; Chromosome Deletion; Animals; Intracellular Signaling Peptides and Proteins; Tumor Suppressor Proteins
PubMed: 38649131
DOI: 10.1016/j.exphem.2024.104217