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Hematology/oncology and Stem Cell... Dec 2021Gene therapy (GT) has been reported to improve bone marrow function in individuals with Fanconi anemia (FA); however, its clinical application is still in the initial...
Gene therapy (GT) has been reported to improve bone marrow function in individuals with Fanconi anemia (FA); however, its clinical application is still in the initial stages. We conducted this systematic review, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to assess the long-term safety and clinical outcomes of GT in FA patients. Electronic searches from PubMed, Web of Science, Cochrane Library, and Google Scholar were conducted and full texts of articles meeting our inclusion criteria were reviewed. Three clinical trials were included, with a total of nine patients and mean age of 10.7 ± 5.7 years. All patients had lentiviral-mediated GT. A 1-year follow-up showed stabilization in blood lineages, without any serious adverse effects from GT. A metaregression analysis could not be conducted, as very little long-term follow-up data of patients was observed, and the median survival rate could not be calculated. Thus, we can conclude that GT seems to be a safe procedure in FA; however, further research needs to be conducted on the longitudinal clinical effects of GT in FA, for a better insight into its potential to become a standard form of treatment.
Topics: Adolescent; Child; Child, Preschool; Fanconi Anemia; Genetic Therapy; Humans
PubMed: 33736979
DOI: 10.1016/j.hemonc.2021.02.001 -
Frontiers in Neurology 2020This study reported two cases of intracranial thrombotic events of aplastic anemia (AA) under therapy with cyclosporine-A (CsA) and reviewed both drug-induced cerebral...
This study reported two cases of intracranial thrombotic events of aplastic anemia (AA) under therapy with cyclosporine-A (CsA) and reviewed both drug-induced cerebral venous thrombosis (CVT) and CsA-related thrombotic events systematically. We searched PubMed Central (PMC) and EMBASE up to Sep 2019 for publications on drug-induced CVT and Cs-A-induced thrombotic events. Medical subject headings and Emtree headings were used with the following keywords: "cyclosporine-A" and "cerebral venous thrombosis OR cerebral vein thrombosis" and "stroke OR Brain Ischemia OR Brain Infarction OR cerebral infarction OR intracerebral hemorrhage OR intracranial hemorrhage." We found that CsA might be a significant risk factor in inducing not only CVT but also cerebral arterial thrombosis in patients with AA.
PubMed: 33643175
DOI: 10.3389/fneur.2020.563037 -
Stem Cell Research & Therapy Feb 2021Mesenchymal stromal cells (MSCs) are an emerging prophylaxis option for graft-versus-host disease (GVHD) in haplo-identical hematopoietic stem cell transplantation... (Meta-Analysis)
Meta-Analysis
Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?-a systematic review and meta-analysis.
BACKGROUND
Mesenchymal stromal cells (MSCs) are an emerging prophylaxis option for graft-versus-host disease (GVHD) in haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) recipients with severe aplastic anemia (SAA), but studies have reported inconsistent results. This systematic review and meta-analysis evaluates the efficacy of MSCs as prophylaxis for GVHD in SAA patients with haplo-HSCT.
METHODS
Studies were retrieved from PubMed, EMBASE, Cochrane, Web of Science, and http://clinicaltrials.gov from establishment to February 2020. Twenty-nine single-arm studies (n = 1456) were included, in which eight (n = 241) studies combined with MSCs and eleven (n = 1215) reports without MSCs in haplo-HSCT for SAA patients. The primary outcomes were the incidences of GVHD. Other outcomes included 2-year overall survival (OS) and the incidence of cytomegalovirus (CMV) infection. Odds ratios (ORs) were calculated to compare the results pooled through random or fixed effects models.
RESULTS
Between MSCs and no MSCs groups, no significant differences were found in the pooled incidences of acute GVHD (56.0%, 95% CI 48.6-63.5% vs. 47.2%, 95% CI 29.0-65.4%; OR 1.43, 95% CI 0.91-2.25; p = 0.123), grade II-IV acute GVHD (29.8%, 95% CI 24.1-35.5% vs. 30.6%, 95% CI 26.6-34.6%; OR 0.97, 95% CI 0.70-1.32; p = 0.889), and chronic GVHD (25.4%, 95% CI 19.8-31.0% vs. 30.0%, 95% CI 23.3-36.6%; OR 0.79, 95% CI 0.56-1.11; p = 0.187). Furtherly, there was no obvious difference in 2-year OS (OR 0.98, 95% CI 0.60-1.61; p = 1.000) and incidence of CMV infection (OR 0.61, 95% CI 0.40-1.92; p = 0.018).
CONCLUSIONS
Our meta-analysis indicates that the prophylactic use of MSC co-transplantation is not an effective option for SAA patients undergoing haplo-HSCT. Hence, the general co-transplantation of MSCs for SAA haplo-HSCT recipients may lack evidence-based practice.
Topics: Anemia, Aplastic; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Transplantation Conditioning
PubMed: 33541414
DOI: 10.1186/s13287-021-02170-7 -
Cardiovascular & Hematological Agents... 2021Immune thrombocytopenia is an immune condition where antibodies are produced against platelets. Eltrombopag is a thrombopoietin receptor agonist that stimulates and... (Meta-Analysis)
Meta-Analysis
Immune thrombocytopenia is an immune condition where antibodies are produced against platelets. Eltrombopag is a thrombopoietin receptor agonist that stimulates and promotes platelet production approved for treating thrombocytopenia in patients with chronic immune thrombocytopenia, where other treatments such as corticosteroids, splenectomy or immunoglobulins are inadequate. The aim of this meta-analysis was to evaluate the efficacy and safety of the eltrombopag in adults and children with immune thrombocytopenia. We included 7 studies with a total of 765 patients (606 adults and 159 children). We evaluated the number of patients that achieved a post-treatment platelet count equal or above 50x10/L (primary result-target) without the need of rescue treatment for at least 4 weeks. Our data showed that patients who received eltrombopag were almost 4 times more probable in achieving the primary target when compared to patients who received placebo (RR 3.84, 95% CI 2.39 to 6.14; I = 46%). The number of patients needed rescue treatment and the number of bleeding incidents were reduced in the group that received eltrombopag when compared to those who received placebo (RR 0.40, 95% CI 0.25 to 0.62; I = 40%) (RR 0.74, 95% CI 0.62 to 0.89; I = 68%). The total number of side effects did not statistically differ between the two groups (RR 0.99, 95% CI 0.90 to 1.08; I = 14%). Our findings were similar to previously published studies and confirm that eltrombopag is safe and efficient in immune thrombocytopenia. However, more clinical trials are needed in order to enhance our findings.
Topics: Adult; Benzoates; Child; Humans; Hydrazines; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Receptors, Thrombopoietin; Treatment Outcome
PubMed: 32914722
DOI: 10.2174/1871525718666200910161540 -
Acta Haematologica 2021PNH clones, also aptly called "escape clones," are evidence of acquired immune-mediated bone marrow failure and have a high prevalence in patients with aplastic anemia... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
PNH clones, also aptly called "escape clones," are evidence of acquired immune-mediated bone marrow failure and have a high prevalence in patients with aplastic anemia (AA). Several studies have reported contradictory results regarding the impact of PNH clones on AA patients with immunosuppression treatment, and PNH clones have not been confirmed as positive predictors of response in the AA guidelines of the British Society for Standards in Haematology.
METHODS
We performed a meta-analysis to address this issue by searching for articles in PubMed, EMBASE, The Coch-rane Library, Web of Science, and ClinicalTrials.gov, and for abstracts from the annual meetings of the American Society of Hematology and the European Hematology Association. We included 1,236 participants from 11 cohort-controlled studies. Our primary outcome was the 6-month hematologic response with a secondary outcome of the mortality rate within 3 months.
RESULTS
A better response rate was observed in the PNH+ group than in the PNH- group (odds ratio [OR] 2.85; 95% confidence interval [CI] 2.17-3.75; p < 0.00001), and further subgroup analysis strengthened the outcome, with minor heterogeneity in non-Asian countries. In contrast, the early mortality was not significantly different between the PNH+ and PNH- groups (OR 0.54; 95% CI 0.26-1.10; p = 0.09).
CONCLUSIONS
The meta-analysis suggested an evidence-based role for PNH clones in predicting a better response in AA patients with immunosuppression.
Topics: Anemia, Aplastic; Clonal Evolution; Combined Modality Therapy; Disease Susceptibility; Female; Hemoglobinuria, Paroxysmal; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Publication Bias; Treatment Outcome
PubMed: 32877903
DOI: 10.1159/000506387 -
Bone Marrow Transplantation Oct 2020Aplastic anemia (AA) is a serious hematological disorder, which is solely cured by hematopoietic stem cell transplantation (HSCT). Haploidentical HSCT is an emerging... (Meta-Analysis)
Meta-Analysis Review
Haploidentical hematopoietic stem cell transplantation in aplastic anemia: a systematic review and meta-analysis of clinical outcome on behalf of the severe aplastic anemia working party of the European group for blood and marrow transplantation (SAAWP of EBMT).
Aplastic anemia (AA) is a serious hematological disorder, which is solely cured by hematopoietic stem cell transplantation (HSCT). Haploidentical HSCT is an emerging modality with encouraging outcomes in several blood conditions. The present study aims to comprehensively assess the feasibility and safety of haploidentical HSCT in patients with severe and very severe AA. It is a systematic review and meta-analysis of studies related to haploidentical stem cell transplantation in idiopathic AA investigating rates of successful engraftment, acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), transplant-related mortality (TRM), and posttransplantation viral infections (including cytomegalovirus [CMV]) in patients with AA. The effects of reduced-intensity conditioning (RIC) and nonmyeloablative conditioning (NMA), as well as various GvHD prophylaxis regimens on these outcomes were evaluated. In total 15 studies were identified, (577 patients, 58.9% males), successful engraftment was observed in 97.3% of patients (95% CI, 95.9-98.7) while grades II-IV aGvHD and cGvHD were reported in 26.6% and 25.0%, respectively. The pooled incidence of TRM was 6.7% per year (95% CI, 4.0-9.4). RIC regimens were associated with higher proportions of successful engraftment (97.7% vs 91.7%, P = 0.03) and aGvHD (29.5% vs 18.7%, P = 0.008) when compared with NMA regimens with no differences in cGvHD or mortality incidence. When compared with methotrexate-containing regimens and other regimens, posttransplant cyclophosphamide-containing regimens reduced the rates of aGvHD (28.6%, 27.8%, and 12.8%, respectively, P = 0.02), CMV viremia (55.7%, 38.6%, and 10.4%, respectively, P < 0.001), and CMV disease in initially viremic patients (2.1%, 33.0%, and 0%, respectively, P < 0.001). We have concluded that Haploidentical HSCT was associated with promising outcomes in terms of successful engraftment and reduced complications. Future prospective trials are needed to identify the preferred conditioning regimen, GvHD prophylaxis, and graft source in the setting of haploidentical transplant for AA.
Topics: Anemia, Aplastic; Bone Marrow; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Transplantation Conditioning
PubMed: 32346079
DOI: 10.1038/s41409-020-0897-2 -
BMC Immunology Mar 2020Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and immunosuppressive therapy (IST) are two major competing treatment strategies for acquired aplastic... (Review)
Review
BACKGROUND
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and immunosuppressive therapy (IST) are two major competing treatment strategies for acquired aplastic anemia (AA). Whether allo-HSCT is superior to IST as a front-line treatment for patients with AA has been a subject of debate. To compare the efficacy and safety of allo-HSCT with that of IST as a front-line treatment for patients with AA, we performed a meta-analysis of available studies that examined the impact of the two major competing treatment strategies for AA.
RESULTS
Fifteen studies including a total of 5336 patients were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival (OS) was 0.4 (95% CI 0.074-0.733, P = 0.016, I = 58.8%) and the pooled HR for failure-free survival (FFS) was 1.962 (95% CI 1.43-2.493, P = 0.000, I = 0%). The pooled relative risk (RR) for overall response rate (ORR) was 1.691 (95% CI 1.433-1.996, P = 0.000, I = 11.6%).
CONCLUSION
Although survival was significantly longer among AA patients undergoing first-line allo-HSCT compared to those undergoing first-line IST, the selection of initial treatment for patients with newly diagnosed AA still requires comprehensive evaluation of donor availability, patient age, expected quality of life, risk of disease relapse or clonal evolution after IST, and potential use of adjunctive eltrombopag.
Topics: Anemia, Aplastic; Animals; Benzoates; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Immunosuppression Therapy; Pyrazoles; Transplantation, Homologous
PubMed: 32138642
DOI: 10.1186/s12865-020-0340-x -
Annals of Hematology May 2020Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital...
Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1-6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs.
Topics: Bone Marrow Cells; Fanconi Anemia; Hematologic Neoplasms; Hematopoietic Stem Cells; Humans; Mosaicism
PubMed: 32065290
DOI: 10.1007/s00277-020-03954-2 -
The Cochrane Database of Systematic... Nov 2019Sickle cell disease (SCD) is a group of inherited disorders of haemoglobin (Hb) structure in a person who has inherited two mutant globin genes (one from each parent),... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sickle cell disease (SCD) is a group of inherited disorders of haemoglobin (Hb) structure in a person who has inherited two mutant globin genes (one from each parent), at least one of which is always the sickle mutation. It is estimated that between 5% and 7% of the world's population are carriers of the mutant Hb gene, and SCD is the most commonly inherited blood disorder. SCD is characterized by distorted sickle-shaped red blood cells. Manifestations of the disease are attributed to either haemolysis (premature red cell destruction) or vaso-occlusion (obstruction of blood flow, the most common manifestation). Shortened lifespans are attributable to serious comorbidities associated with the disease, including renal failure, acute cholecystitis, pulmonary hypertension, aplastic crisis, pulmonary embolus, stroke, acute chest syndrome, and sepsis. Vaso-occlusion can lead to an acute, painful crisis (sickle cell crisis, vaso-occlusive crisis (VOC) or vaso-occlusive episode). Pain is most often reported in the joints, extremities, back or chest, but it can occur anywhere and can last for several days or weeks. The bone and muscle pain experienced during a sickle cell crisis is both acute and recurrent. Key pharmacological treatments for VOC include opioid analgesics, non-opioid analgesics, and combinations of drugs. Non-pharmacological approaches, such as relaxation, hypnosis, heat, ice and acupuncture, have been used in conjunction to rehydrating the patient and reduce the sickling process.
OBJECTIVES
To assess the analgesic efficacy and adverse events of pharmacological interventions to treat acute painful sickle cell vaso-occlusive crises in adults, in any setting.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, Embase via Ovid and LILACS, from inception to September 2019. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.
SELECTION CRITERIA
Randomized, controlled, double-blind trials of pharmacological interventions, of any dose and by any route, compared to placebo or any active comparator, for the treatment (not prevention) of painful sickle cell VOC in adults.
DATA COLLECTION AND ANALYSIS
Three review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio (RR) and number needed to treat for one additional event, using standard methods. Our primary outcomes were participant-reported pain relief of 50%, or 30%, or greater; Patient Global Impression of Change (PGIC) very much improved, or much or very much improved. Our secondary outcomes included adverse events, serious adverse events, and withdrawals due to adverse events. We assessed GRADE and created three 'Summary of findings' tables.
MAIN RESULTS
We included nine studies with data for 638 VOC events and 594 participants aged 17 to 42 years with SCD presenting to a hospital emergency department in a painful VOC. Three studies investigated a non-steroidal anti-inflammatory drug (NSAID) compared to placebo. One study compared an opioid with a placebo, two studies compared an opioid with an active comparator, two studies compared an anticoagulant with a placebo, and one study compared a combination of three drugs with a combination of four drugs. Risk of bias across the nine studies varied. Studies were primarily at an unclear risk of selection, performance, and detection bias. Studies were primarily at a high risk of bias for size with fewer than 50 participants per treatment arm; two studies had 50 to 199 participants per treatment arm (unclear risk). Non-steroidal anti-inflammatory drugs (NSAID) compared with placebo No data were reported regarding participant-reported pain relief of 50% or 30% or greater. The efficacy was uncertain regarding PGIC very much improved, and PGIC much or very much improved (no difference; 1 study, 21 participants; very low-quality evidence). Very low-quality, uncertain results suggested similar rates of adverse events across both the NSAIDs group (16/45 adverse events, 1/56 serious adverse events, and 1/56 withdrawal due to adverse events) and the placebo group (19/45 adverse events, 2/56 serious adverse events, and 1/56 withdrawal due to adverse events). Opioids compared with placebo No data were reported regarding participant-reported pain relief of 50% or 30%, PGIC, or adverse events (any adverse event, serious adverse events, and withdrawals due to adverse events). Opioids compared with active comparator No data were reported regarding participant-reported pain relief of 50% or 30% or greater. The results were uncertain regarding PGIC very much improved (33% of the opioids group versus 19% of the placebo group). No data were reported regarding PGIC much or very much improved. Very low-quality, uncertain results suggested similar rates of adverse events across both the opioids group (9/66 adverse events, and 0/66 serious adverse events) and the placebo group (7/64 adverse events, 0/66 serious adverse events). No data were reported regarding withdrawal due to adverse events. Quality of the evidence We downgraded the quality of the evidence by three levels to very low-quality because there are too few data to have confidence in results (e.g. too few participants per treatment arm). Where no data were reported for an outcome, we had no evidence to support or refute (quality of the evidence is unknown).
AUTHORS' CONCLUSIONS
This review identified only nine studies, with insufficient data for all pharmacological interventions for analysis. The available evidence is very uncertain regarding the efficacy or harm from pharmacological interventions used to treat pain related to sickle cell VOC in adults. This area could benefit most from more high quality, certain evidence, as well as the establishment of suitable registries which record interventions and outcomes for this group of people.
Topics: Acute Pain; Analgesics; Analgesics, Opioid; Anemia, Sickle Cell; Anti-Inflammatory Agents, Non-Steroidal; Humans; Pain Management; Pain Measurement; Peripheral Vascular Diseases; Randomized Controlled Trials as Topic
PubMed: 31742673
DOI: 10.1002/14651858.CD012187.pub2 -
Frontiers in Immunology 2019Autoimmune diseases are usually complex and multifactorial, characterized by aberrant production of autoreactive immune cells and/or autoantibodies against healthy cells...
Autoimmune diseases are usually complex and multifactorial, characterized by aberrant production of autoreactive immune cells and/or autoantibodies against healthy cells and tissues. However, the pathogenesis of autoimmune diseases has not been clearly elucidated. The activation, differentiation, and development of CD8+ T cells can be affected by numerous inflammatory cytokines, transcription factors, and chemokines. In recent years, epigenetic modifications have been shown to play an important role in the fate of CD8+ T cells. The discovery of these modifications that contribute to the activation or suppression of CD8+ cells has been concurrent with the increasing evidence that CD8+ T cells play a role in autoimmunity. These relationships have been studied in various autoimmune diseases, including multiple sclerosis (MS), systemic sclerosis (SSc), type 1 diabetes (T1D), Grave's disease (GD), systemic lupus erythematosus (SLE), aplastic anemia (AA), and vitiligo. In each of these diseases, genes that play a role in the proliferation or activation of CD8+ T cells have been found to be affected by epigenetic modifications. Various cytokines, transcription factors, and other regulatory molecules have been found to be differentially methylated in CD8+ T cells in autoimmune diseases. These genes are involved in T cell regulation, including interferons, interleukin (IL),tumor necrosis factor (TNF), as well as linker for activation of T cells (LAT), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and adapter proteins. MiRNAs also play a role in the pathogenesis of these diseases and several known miRNAs that are involved in these diseases have also been shown to play a role in CD8+ regulation.
Topics: Animals; Autoimmune Diseases; Autoimmunity; CD8-Positive T-Lymphocytes; Cell Differentiation; Epigenesis, Genetic; Epigenomics; Humans; T-Lymphocytes, Regulatory
PubMed: 31057561
DOI: 10.3389/fimmu.2019.00856