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Leukemia Research Dec 2022According to the current treatment recommendations, anagrelide, an oral antiplatelet agent, is recommended as a second-line therapy for patients with high-risk essential...
According to the current treatment recommendations, anagrelide, an oral antiplatelet agent, is recommended as a second-line therapy for patients with high-risk essential thrombocythemia experiencing intolerance or refractoriness to first-line approach, such as hydroxyurea or pegylated interferon alpha-2a. If there is a need for introduction of cytoreductive treatment in young patients with a perspective of lifelong exposure, both the efficacy and long-term outcomes should be known. We present the analysis of 48 young patients, diagnosed with essential thrombocythemia below the age of 60, who were exposed to anagrelide treatment for over 10 years. Our observations show that the highest proportion of complete remissions without adverse events and disease progression is seen in the JAK2-mutated patients. By evaluating the changes in hemoglobin concentration and serum erythropoietin throughout the study, we were able to reveal the development of progressive anemia, resulting from diminished susceptibility to erythropoietin and unrelated to bone marrow fibrosis, in patients harboring CALR mutation. Additionally, occurrence of new bone marrow fibrosis was confirmed in seven JAK2-unmutated patients at the end of the study. In summary, in young patient population, we recommend limiting the use of anagrelide to JAK2-mutated subgroup, reducing exposure time and underline the importance of periodic monitoring for the presence of bone marrow fibrosis.
Topics: Child; Humans; Erythropoietin; Platelet Aggregation Inhibitors; Primary Myelofibrosis; Quinazolines; Thrombocythemia, Essential
PubMed: 36183610
DOI: 10.1016/j.leukres.2022.106962 -
International Medical Case Reports... 2022Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) which could complicate surgical procedures due to thrombosis and spontaneous bleeding. However,...
INTRODUCTION
Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) which could complicate surgical procedures due to thrombosis and spontaneous bleeding. However, currently, there is neither concrete guideline nor prerequisite for ET patients who underwent operations.
CASE REPORT
A 48 year-old-female was admitted to the emergency unit on 21 February 2020 due to vomiting and inability to pass gas/stool. The patient previously had an operation for uterine myoma two weeks before which showed thrombocyte count of 688,000/mm. The patient was previously diagnosed with essential thrombocythemia with positive JAK2V617 point mutation on 24 June 2019. Laboratory examination showed thrombocyte 1,134,000/mm and leukocyte 22,700/mm suggestive of neutrophilia. CT scan showed fluid collection with blood density in the abdomen and pelvis. She was then diagnosed with obstructive ileus due to abdominal abscess and intestine adhesion. Adhesiolysis by laparoscopy was performed on 29 February 2020 with thrombocyte count of 727,000/mm. Patient was able to pass flatus and defecate three days post-surgery. However, a decrease of hemoglobin to 8.2 g/dL on 3 March 2020 with thrombocyte count of 700,000/mm was suggestive of internal bleeding. She was discharged three weeks post-surgery after improvement of clinical condition with thrombocyte count of 850,000/mm. She was given hydroxyurea 1000 mg once every two days, aspirin 80 mg OD, anagrelide 1 mg OD, and amlodipine 10 mg OD.
CONCLUSION
Myeloproliferative disease patients with high thrombocyte count are subjected to increased risk of thrombotic complications in perioperative settings, thus perioperative management and risk assessment are important to improve quality of life and prevent complications. Surgery in MPN patients with elevated thrombocytes may be considered if the benefits outweigh the risks. More studies in this field should be conducted in-order to provide more data for a guideline or systematic review/meta-analyses.
PubMed: 36120702
DOI: 10.2147/IMCRJ.S375777 -
Annals of Hematology Nov 2022
Topics: Hemorrhage; Humans; Platelet Aggregation Inhibitors; Quinazolines; Thrombocythemia, Essential; Thrombosis
PubMed: 35978180
DOI: 10.1007/s00277-022-04956-y -
Frontiers in Genetics 2022Glioma is the most malignant cancer of the central nervous system. There are various therapies for treating gliomas, but their outcomes are not satisfactory. Therefore,...
Glioma is the most malignant cancer of the central nervous system. There are various therapies for treating gliomas, but their outcomes are not satisfactory. Therefore, new targets for glioma treatment are needed. This study examined the cadherin-6 (CDH6) expression in gliomas using The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets. CDH6 expression positively correlated with the World Health Organization (WHO) tumor grade and negatively correlated with patient prognosis. A significant decrease in CDH6 promoter methylation was identified with an increase in the WHO grade severity. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that CDH6 might be involved in cell-cell interactions and immune processes in the glioma microenvironment. Weighted gene co-expression network analysis revealed a correlation between CDH6 and cell adhesion molecules, focal adhesions, phosphatidylinositol 3-kinase-protein kinase B signaling pathways, nuclear division, chromosome segregation, mitotic nuclear division, and immune-related pathways. CDH6 strongly correlated with immunosuppressive cells, including regulatory T cells, monocytes, macrophages, tumor-associated macrophages, and myeloid-derived suppressor cells. It also showed correlations with immune-active cells such as B cells, CD8 T cells, and dendritic cells. Single-cell analysis showed that CDH6 was expressed mainly in astrocyte (AC)-like malignant cells. Differentially expressed genes of AC-like malignant cells were found to be associated with stress response, membranous processes, viral infections, and several types of cancers. Potential drugs associated with high CDH6 expression were also predicted, including AMG-22, rutin, CCT128930, deforolimus, bis(maltolato)oxovanadium, anagrelide, vemurafenib, CHIR-98014, and AZD5582. Thus, this study showed that CDH6 correlates with glioma immune infiltration, it is expressed mainly in AC-like malignant cells, and it may act as a new target for glioma therapy.
PubMed: 35938030
DOI: 10.3389/fgene.2022.949552 -
Future Oncology (London, England) Sep 2022Patients diagnosed with high-risk essential thrombocythemia (ET) have limited treatment options to reduce the risk of thrombosis and lessen the progression of the...
Patients diagnosed with high-risk essential thrombocythemia (ET) have limited treatment options to reduce the risk of thrombosis and lessen the progression of the disease by targeting the molecular source. Hydroxyurea is the recommended treatment, but many patients experience resistance or intolerance. Anagrelide is an approved second-line option for ET, but concerns of a higher frequency of disease transformation may affect its role as a suitable long-term option. Interferons have been evaluated in myeloproliferative neoplasms for over 30 years, but early formulations had safety and tolerability issues. SURPASS-ET (NCT04285086) is a phase III, open-label, multicenter, global, randomized, active-controlled trial that will evaluate the safety, efficacy, tolerability and pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide as second-line therapy in high-risk ET.
Topics: Clinical Trials, Phase III as Topic; Humans; Hydroxyurea; Multicenter Studies as Topic; Quinazolines; Randomized Controlled Trials as Topic; Thrombocythemia, Essential
PubMed: 35924546
DOI: 10.2217/fon-2022-0596 -
Cureus Jun 2022Anagrelide is an inhibitor of the phosphodiesterase-3 (PDE-3) enzyme that suppresses megakaryocytes; hence it is used in the treatment of essential thrombocythemia....
Anagrelide is an inhibitor of the phosphodiesterase-3 (PDE-3) enzyme that suppresses megakaryocytes; hence it is used in the treatment of essential thrombocythemia. Anagrelide can cause positive inotropic and chronotropic effects on the cardiovascular system. Its cardiovascular side effects are rare and include palpitations, tachyarrhythmias, cardiomyopathy, angina, and heart failure. We report the case of a 71-year-old female who presented with sudden onset chest pain. Her only outpatient medications included anagrelide and aspirin. She was found to have supraventricular tachycardia (SVT) with aberrancy that responded to beta-blockers. The chest X-ray, computed tomography angiogram (CTA), and echocardiogram were unremarkable. Her arrhythmia may be attributed to the anagrelide in the absence of any cardiovascular findings.
PubMed: 35747119
DOI: 10.7759/cureus.26119 -
Leukemia Research Aug 2022Anagrelide (ANA) is a platelet-specific cytoreductive agent utilized in the guideline-directed management of high-risk essential thrombocythemia. In the context of...
Anagrelide (ANA) is a platelet-specific cytoreductive agent utilized in the guideline-directed management of high-risk essential thrombocythemia. In the context of polycythemia vera (PV), ANA is occasionally employed in clinical practice, although data has not consistently demonstrated a benefit to targeting a platelet goal as a therapeutic endpoint. The aim of the current study was to delineate the patterns of ANA use in PV, and to describe outcomes and toxicities. Within a multi-center cohort of 527 patients with PV, 48 received ANA (9 excluded for absent data). 27 (69.2%) had high-risk PV, 10 (25.6%) had prior thrombosis, and none had extreme thrombocytosis, acquired von Willebrand disease, and/or documented resistance to hydroxyurea. While ANA effectively lowered median platelet count, 43.5% of patients had an unresolved thrombocytosis at time of ANA discontinuation. Treatment-emergent adverse events-including headaches, cardiac palpitations and arrhythmias, nausea, vomiting and/or diarrhea-led to ANA discontinuation in 76.9% of patients. Further, three patients experienced arterial thromboses during a median duration of 27.5 months of ANA therapy. In conclusion, this study highlights ANA's restrictive tolerability profile which, compounded by the absence of clear advantage to strict platelet control in PV, suggests the use of ANA should be limited in this setting.
Topics: Cytoreduction Surgical Procedures; Humans; Polycythemia Vera; Quinazolines; Thrombocythemia, Essential; Thrombocytosis; Thrombosis
PubMed: 35717689
DOI: 10.1016/j.leukres.2022.106903 -
Leukemia Research Jul 2022Subsequent blast (BP) or accelerated phase (AP) is a severe complication of Philadelphia-negative myeloproliferative neoplasms (MPNs). The prognosis is generally dismal,...
Subsequent blast (BP) or accelerated phase (AP) is a severe complication of Philadelphia-negative myeloproliferative neoplasms (MPNs). The prognosis is generally dismal, but hypomethylating agents (HMAs) may induce a long-lasting response in a minority of patients. Here, we report a cohort of six patients with BP/AP-MPN who experienced MPN relapse after a leukemia response was obtained with azacytidine. Five of the patients achieved complete remission despite the presence of characteristics associated with poor prognosis, such as complex and monosomal karyotypes, TP53 mutations, and EVI1 overexpression. These remissions persisted for over five years in four of the 6 patients. All patients showed rapid reemergence of MPN within a median of two months with thrombocytosis requiring the addition of anagrelide, hydroxyurea, or ruxolitinib given continuously in parallel with the azacytidine cycle. Serial JAK2 V617F allelic burden measurements showed little variation. Thromboembolic events occurred in 3 patients, one leading to death. These findings confirm that HMA may reverse the disease course in AP/BP-MPN to a more chronic phase that may last for years but also lead to morbidity and mortality. Combining maintenance therapy with HMA and MPN-specific drugs appears to be a possible approach to avoiding leukemia relapse and controlling MPN disease.
Topics: Azacitidine; Humans; Janus Kinase 2; Leukemia; Lymphocyte Activation; Mutation; Myeloproliferative Disorders; Neoplasms; Recurrence
PubMed: 35633618
DOI: 10.1016/j.leukres.2022.106871 -
International Journal of Hematology Oct 2022In Japan, anagrelide has been approved for use in patients with essential thrombocythemia. Here, the safety and efficacy of anagrelide was assessed in clinical practice...
Safety and efficacy of anagrelide in Japanese post-marketing surveillance, with subgroup analyses on the effect of previous cytoreductive therapies, age, and starting dose.
BACKGROUND
In Japan, anagrelide has been approved for use in patients with essential thrombocythemia. Here, the safety and efficacy of anagrelide was assessed in clinical practice as post-marketing surveillance. Subgroup analyses were conducted to compare patients (1) with or without a history of cytoreductive therapy (CRT), (2) <60 or ≥60 years of age, and (3) with an anagrelide starting dose of ≤0.5 mg/day or 1.0 mg/day.
METHODS
Data were collected for all patients who received anagrelide, with an observation period of 12 months after treatment initiation.
RESULTS
Of the 648 patients, 54.3% experienced adverse drug reactions (ADRs). The most commonly reported ADRs were headaches, palpitations, and anemia. No significant difference was observed in overall ADRs across patient subgroups. A significantly higher incidence of headaches was observed in patients < 60 years versus those ≥ 60 years (P < 0.001). The incidence of anemia and serious ADRs were significantly higher in patients ≥ 60 years, and those with a history of CRT (P < 0.05). The discontinuation rate at 6 months was significantly lower in patients started at the lower anagrelide dose (P < 0.05). Platelet counts decreased in all analyzed groups.
CONCLUSIONS
This surveillance showed that anagrelide has a tolerable safety and efficacy profile.
Topics: Cytoreduction Surgical Procedures; Headache; Humans; Japan; Platelet Aggregation Inhibitors; Product Surveillance, Postmarketing; Quinazolines
PubMed: 35624199
DOI: 10.1007/s12185-022-03380-2 -
Therapeutic Advances in Neurological... 2022Cerebrovascular events, especially ischemic stroke, are common complications of essential thrombocythemia (ET). Compared to JAK2V617 F mutation, CALR mutation is...
Cerebrovascular events, especially ischemic stroke, are common complications of essential thrombocythemia (ET). Compared to JAK2V617 F mutation, CALR mutation is considered as a lower risk factor of thrombosis in ET. Until now stroke in ET with CALR mutation has rarely been reported. We retrospectively investigated patients diagnosed with stroke and ET in Xijing hospital of Air Force Medical University, from 2015 to 2021. Clinical characteristics (including medical history, physical and auxiliary examination and prognosis) were recorded and associated literature was reviewed. Among the 19 patients diagnosed with both stroke and ET we retrieved, two cases were positive for CALR mutation. In case 1, a 71-year-old man developed the first ischemic event under the treatment of anagrelide, followed by a hemorrhagic stroke after receiving aspirin and clopidogrel for 4 months. Ischemic stroke reccurred and the neurological function deteriorated progressively. In case 2, a 44-year-old man presented with hypoxic-ischemic encephalopathy due to serious myocardial infarction and subsequent brain imaging indicated three times of ischemic stroke events. The patient gradually got improved through cytoreductive and antiplatelet therapy and rehabilitation. Literature review showed that cerebrovascular event is the most serious neurological complication of ET and may be the presenting symptom. Most of reported cases with ET accompanied by stroke were positive for JAK2 V617 F mutation, but with rare CALR mutation. ET with CALR mutation can cause both hemorrhagic and ischemic stroke. Identification of such rare causes of stroke is of great importance to provide precise and individualized prevention and therapy.
PubMed: 35498365
DOI: 10.1177/17562864221092093