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Journal of Clinical Medicine May 2024Essential thrombocythemia (ET) is a myeloproliferative neoplasm that overproduces platelets and is associated with life-threatening thrombosis. Medical cytoreduction...
Essential thrombocythemia (ET) is a myeloproliferative neoplasm that overproduces platelets and is associated with life-threatening thrombosis. Medical cytoreduction either with hydroxyurea (HU) or anagrelide (AG) is widely used, but drug intolerance or resistance are major concerns. Low-dose combination of HU and AG as an alternative strategy has been explored in various studies. It showed comparable response with acceptable toxicity in second-line settings for patients who experienced side effects from prior monotherapy. In this study, we evaluated the efficacy and safety of upfront combination for ET patients. From January 2018 to June 2022, a total of 241 ET patients with intermediate to high risk were enrolled. We identified 21 patients with initial drug combinations and compared treatment outcomes and adverse events (AEs) between combination and monotherapy groups. The median age was 62 years old (range, 26-87) and median platelet count was 912 × 10/L (range, 520-1720). Overall treatment response did not exhibit significant differences between the groups, although there was a trend towards a lower response rate in patients treated with AG alone at 3 months post-treatment (AG + HU, 85.7% vs. AG alone, 75.4%, = 0.068). AEs of any grade occurred in 52.3% of the combination group, 44.3% of the HU monotherapy group, and 43.4% of the AG single group, respectively. Of note was that the HU plus AG combination group suffered a lower incidence of grade 3-4 AEs compared to the other two groups, with statistical significance ( = 0.008 for HU monotherapy vs. combination therapy and < 0.01 for AG monotherapy vs. combination therapy). Our findings demonstrated that the upfront low-dose combination approach showed feasible clinical outcomes with significantly lower severe AEs compared to conventional monotherapy. These results may offer valuable insights to clinicians for future prospective investigations.
PubMed: 38792442
DOI: 10.3390/jcm13102901 -
International Journal of Molecular... Apr 2024Melanoma, the deadliest type of skin cancer, has a high propensity to metastasize to other organs, including the brain, lymph nodes, lungs, and bones. While progress has...
Melanoma, the deadliest type of skin cancer, has a high propensity to metastasize to other organs, including the brain, lymph nodes, lungs, and bones. While progress has been made in managing melanoma with targeted and immune therapies, many patients do not benefit from these current treatment modalities. Tumor cell migration is the initial step for invasion and metastasis. A better understanding of the molecular mechanisms underlying metastasis is crucial for developing therapeutic strategies for metastatic diseases, including melanoma. The cell adhesion molecule L1CAM (CD171, in short L1) is upregulated in many human cancers, enhancing tumor cell migration. Earlier studies showed that the small-molecule antagonistic mimetics of L1 suppress glioblastoma cell migration in vitro. This study aims to evaluate if L1 mimetic antagonists can inhibit melanoma cell migration in vitro and in vivo. We showed that two antagonistic mimetics of L1, anagrelide and 2-hydroxy-5-fluoropyrimidine (2H5F), reduced melanoma cell migration in vitro. In in vivo allograft studies, only 2H5F-treated female mice showed a decrease in tumor volume.
Topics: Cell Movement; Animals; Humans; Melanoma; Mice; Neural Cell Adhesion Molecule L1; Cell Line, Tumor; Female; Xenograft Model Antitumor Assays; Skin Neoplasms; Pyrimidines
PubMed: 38732030
DOI: 10.3390/ijms25094811 -
CEN Case Reports Apr 2024A 62-year-old female patient with essential thrombocythemia experienced rapid renal dysfunction and was subsequently referred to our hospital. Further investigations did...
A 62-year-old female patient with essential thrombocythemia experienced rapid renal dysfunction and was subsequently referred to our hospital. Further investigations did not reveal any significant abnormalities except for a slight increase in urinary β2-microglobulin levels. A renal biopsy was performed to investigate the cause of her renal dysfunction, revealing acute tubular necrosis, interstitial edema, and arteriosclerosis. No significant glomerular lesions were observed. Immunofluorescence staining and electron microscopy showed no abnormalities. She had been using anagrelide for 4 years, and her dosage was increased from 2.0 to 3.0 mg/day 10 months before her initial admission. Her renal function began to deteriorate 2 months after the anagrelide dosage increase. Although 0.625 mg of bisoprolol was initiated for tachycardia 3 months after the anagrelide dosage adjustment, we suspected that the acute tubular necrosis was associated with anagrelide administration. After transitioning from anagrelide to hydroxyurea and discontinuing bisoprolol, her renal function improved. This case suggests the importance of considering anagrelide as a potential cause of renal dysfunction in patients using this medication. Therefore, renal biopsy, combined with a comprehensive medical history, is crucial for evaluating the etiology of renal injury in such cases.
PubMed: 38658458
DOI: 10.1007/s13730-024-00881-3 -
European Journal of Case Reports in... 2024Anagrelide is a medication primarily used to manage thrombocytosis, an abnormal increase in platelet levels in the blood. It is often prescribed for patients with...
UNLABELLED
Anagrelide is a medication primarily used to manage thrombocytosis, an abnormal increase in platelet levels in the blood. It is often prescribed for patients with myeloproliferative disorders, such as essential thrombocythaemia (ET). Given the heightened susceptibility to thromboembolism associated with this condition, the primary emphasis in treatment revolves around reducing the risk of thrombotic events through the administration of cytotoxic agents. While anagrelide is generally effective in reducing platelet counts, it comes with potential side effects, including an increased risk of certain thrombotic events. Anagrelide acts by inhibiting megakaryocyte maturation and platelet release, thereby reducing platelet production. However, this platelet-lowering effect may be accompanied by an increase in platelet activation and reactivity, which could contribute to a prothrombotic state. We present a case of a 60-year-old female with a history of ET, managed with anagrelide and hydroxyurea therapy, who experienced an acute ST-elevation myocardial infarction.
LEARNING POINTS
The dual role of anagrelide: although anagrelide is effective in lowering platelet levels in essential thrombocythaemia, it can increase platelet activation, raising thrombotic risk. Clinicians need to monitor patients closely for thrombotic events.Balancing efficacy and side effects: the risk of severe side effects such as myocardial infarction, as seen in this case report, necessitates a balanced approach in using anagrelide, weighing its benefits against potential risks.
PubMed: 38455691
DOI: 10.12890/2024_004340 -
Molecular and Clinical Oncology Sep 2023Chronic myeloproliferative neoplasms (MPN) include polycythemia vera (PV), primary myelofibrosis, essential thrombocythemia (ET) and chronic myeloid leukemia (CML)....
Chronic myeloproliferative neoplasms (MPN) include polycythemia vera (PV), primary myelofibrosis, essential thrombocythemia (ET) and chronic myeloid leukemia (CML). Overlapping MPNs are rare; however, they can occur in the same individual. The present case report describes a patient with both triple-negative ET and CML. A 64-year-old woman was followed-up at our hematology clinic at Feist Weiller Cancer Center, Louisiana State University Health Shreveport (Shreveport, LA, USA) since 2000 after she was diagnosed with JAK2V617F-negative ET. The patient remained stable on hydroxyurea until 2012, when they underwent a bone marrow biopsy for progressively increasing white blood cell counts, and the pathology was consistent with CML; PCR for BCR-ABL was positive for both P210 and P190 transcripts. The patient was then initiated on dasatinib. After dasatinib, they were given a trial of imatinib, and were later transitioned to nilotinib and finally to bosutinib (2019) due to unchanged thrombocytosis. Next-generation sequencing from a bone marrow biopsy in 2019 demonstrated an EZH2 mutation that may be associated with triple-negative ET. CML was in major molecular response at that time. The patient was continued on bosutinib with hydroxyurea, after which hydroxyurea was changed to anagrelide due to worsening anemia and persistent thrombocytosis. However, bosutinib and anagrelide were discontinued due to worsening pulmonary hypertension. The patient was noted to have peripheral blasts of 14% by flow cytometry, after which they underwent a repeat bone marrow biopsy in 2022, which showed extensive myelofibrosis. BCR-ABL transcripts were undetectable. Given their accelerated myelofibrosis, the patient was started on a hypomethylating agent, decitabine/cedazuridine, along with darbepoetin for anemia in June 2022. Given their persistent thrombocytosis, the patient was also started on peginterferon α. Most studies reporting two clonal processes in the same patient have been for PV and CML. To the best of our knowledge, this is the first reported case of triple-negative ET with double transcript CML in the same individual.
PubMed: 37614369
DOI: 10.3892/mco.2023.2663 -
Frontiers in Oncology 2023Knowledge on the myeloproliferative neoplasms (MPNs) - polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) - has accumulated since the... (Review)
Review
Knowledge on the myeloproliferative neoplasms (MPNs) - polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) - has accumulated since the discovery of the JAK/STAT-activating mutations associated with MPNs: V617F, observed in PV, ET and PMF; and the and mutations, found in ET and PMF. The intriguing lack of disease specificity of these mutations, and of the chronic inflammation associated with MPNs, triggered a quest for finding what precisely determines that MPN patients develop a PV, ET or PMF phenoptype. The mechanisms of action of MPN-driving mutations, and concomitant mutations (, others), have been extensively studied, as well as the role played by these mutations in inflammation, and several pathogenic models have been proposed. In parallel, different types of drugs have been tested in MPNs (JAK inhibitors, interferons, hydroxyurea, anagrelide, azacytidine, combinations of those), some acting on both JAK2 and inflammation. Yet MPNs remain incurable diseases. This review aims to present current, detailed knowledge on the pathogenic mechanisms specifically associated with PV, ET or PMF that may pave the way for the development of novel, curative therapies.
PubMed: 37284191
DOI: 10.3389/fonc.2023.1196817 -
Clinical Case Reports Apr 2023Pericardial effusion leading to cardiac tamponade can occur due to a multitude of etiologies, one of which is medication adverse effects. In patients with comorbid...
Pericardial effusion leading to cardiac tamponade can occur due to a multitude of etiologies, one of which is medication adverse effects. In patients with comorbid conditions, this can prove to be a challenge in its co-management along with the primary disease. We present a rare case of anagrelide-induced pericardial effusion that is presented with tamponade physiology in a patient with essential thrombocythemia. After cautiously weighing the risks and benefits of further invasive interventions following an unsuccessful pericardiocentesis, the decision was to stop anagrelide while managing the pericardial effusion medically. Therefore, managing pericardial effusion should be tailored to each patient individually through shared decision-making.
PubMed: 37102091
DOI: 10.1002/ccr3.7246 -
ACS Medicinal Chemistry Letters Apr 2023The mode of action by which the orphan drug anagrelide (), a potent cAMP phosphodiesterase 3A inhibitor, reduces blood platelet count in humans is not well understood....
The mode of action by which the orphan drug anagrelide (), a potent cAMP phosphodiesterase 3A inhibitor, reduces blood platelet count in humans is not well understood. Recent studies indicate that stabilizes a complex between PDE3A and Schlafen 12, protecting it from degradation while activating its RNase activity.
PubMed: 37077378
DOI: 10.1021/acsmedchemlett.3c00092 -
Journal of Clinical and Experimental... 2023TAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. We encountered a case of...
TAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. We encountered a case of calreticulin mutation-positive essential thrombocythemia (ET) with TAFRO syndrome-like features, followed by a rapid fatal course. The patient had been on anagrelide therapy for approximately three years for management of ET; however, she suddenly stopped going for follow-up and discontinued the medicine for a year. She presented with fever and hypotension, suggestive of septic shock, and was transferred to our hospital. The platelet count at the time of admission to another hospital was 50 × 10 / μL; however, it decreased to 25 × 10 / μL upon transfer to our hospital and further decreased to 5 × 10 / μL on the day of her death. In addition, the patient showed remarkable systemic edema and progression of organomegaly. Her condition suddenly worsened and led to her death on the 7th day of hospitalization. Postmortem, serum and pleural effusion interleukin (IL)-6 and vascular endothelial growth factor (VEGF) levels were significantly increased. Consequently, a diagnosis of TAFRO syndrome, since she met the diagnostic criteria for clinical findings and had high cytokine concentrations. Dysregulation of cytokine networks has also been reported in ET. Therefore, concurrent ET and TAFRO syndrome may have further triggered cytokine storms and contributed to the aggravation of the disease on development of TAFRO syndrome. To the best of our knowledge, this is the first report of complications seen in a patient with TAFRO syndrome due to ET.
Topics: Female; Humans; Thrombocythemia, Essential; Vascular Endothelial Growth Factor A; Castleman Disease; Edema; Fever; Cytokines
PubMed: 36990774
DOI: 10.3960/jslrt.22029 -
Hematology Reports Mar 2023Myeloproliferative neoplasms (MPN) such as essential thrombocythemia (ET) and polycythemia vera (PV) are rare during pregnancy. However, they are harmful because they...
Myeloproliferative neoplasms (MPN) such as essential thrombocythemia (ET) and polycythemia vera (PV) are rare during pregnancy. However, they are harmful because they are associated with an increased risk of thromboembolic, hemorrhagic, or microcirculatory disturbances or placental dysfunction leading to fetal growth restriction or loss. Low-dose aspirin and low-molecular-weight heparin (LMWH) are recommended to reduce pregnancy complications, and interferon (IFN) is the only treatment option for cytoreductive therapy based on the likelihood of live birth in pregnant women with MPN. Since ropeginterferon alfa-2b is the only available IFN in South Korea, we present a case report of ropeginterferon alfa-2b use during pregnancy in an MPN patient. A 40-year-old woman who had been diagnosed with low-risk PV in 2017 and had been maintained on phlebotomy, hydroxyurea (HU), and anagrelide (ANA) for 4 years was confirmed as 5 weeks pregnant on 9 December 2021. After stopping treatment with HU and ANA, the patient showed a rapid increase in platelet count (1113 × 10/L to 2074 × 10/L, normal range, 150-450 × 10/L) and white blood cell count (21.93 × 10/L to 35.55 × 10/L, normal range, 4.0-10.0 × 10/L). Considering the high risk of complications, aggressive cytoreductive treatment was required, for which we chose ropeginterferon alfa-2b, as it is the only available IFN agent in South Korea. The patient underwent 8 cycles of ropeginterferon alfa-2b over 6 months during pregnancy and delivered without any neonatal or maternal complications. This case report highlights the importance of considering treatment options for MPN patients who are pregnant or planning a pregnancy, as well as the need for further investigation into the safety and efficacy of ropeginterferon alfa-2b in this population.
PubMed: 36975731
DOI: 10.3390/hematolrep15010018