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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 -
British Journal of Haematology May 2024Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by an increased risk of vascular complications and a tendency to progress to myelofibrosis... (Review)
Review
Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by an increased risk of vascular complications and a tendency to progress to myelofibrosis and acute leukaemia. ET patients have traditionally been stratified into two thrombosis risk categories based on age older than 60 years and a history of thrombosis. More recently, the revised IPSET-thrombosis scoring system, which accounts for the increased risk linked to the JAK2 mutation, has been incorporated into most expert recommendations. However, there is increasing evidence that the term ET encompasses different genomic entities, each with a distinct clinical course and prognosis. Moreover, the effectiveness and toxicity of cytoreductive and anti-platelet treatments differ depending on the molecular genotype. While anti-platelets and conventional cytoreductive agents, mainly hydroxycarbamide (hydroxyurea), anagrelide and pegylated interferon, remain the cornerstone of treatment, recent research has shed light on the effectiveness of novel therapies that may help improve outcomes. This comprehensive review focuses on the evolving landscape of treatment strategies in ET, with an emphasis on the role of molecular profiling in guiding therapeutic decisions. Besides evidence-based management according to revised IPSET-thrombosis stratification, we also provide specific observations for those patients with CALR-, MPL-mutated and triple-negative ET, as well as cases with high-risk mutations.
Topics: Humans; Thrombocythemia, Essential; Janus Kinase 2; Platelet Aggregation Inhibitors; Mutation; Receptors, Thrombopoietin; Calreticulin
PubMed: 38586911
DOI: 10.1111/bjh.19403 -
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 -
Annals of Hematology Mar 2024Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including...
ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options.
Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.
PubMed: 38438627
DOI: 10.1007/s00277-024-05665-4 -
Hematology. American Society of... Dec 2023Thrombotic complications are the primary contributor to morbidity and mortality in essential thrombocythemia (ET) and polycythemia vera (PV). Cytoreductive therapy is... (Review)
Review
Thrombotic complications are the primary contributor to morbidity and mortality in essential thrombocythemia (ET) and polycythemia vera (PV). Cytoreductive therapy is the main tool for primary or tertiary thrombosis prevention in these diseases. In general, high-thrombotic-risk patients and those with symptoms that may be ameliorated from cytoreductive therapy are candidates for this treatment, although the decision is highly individualized. Approved options for cytoreduction in ET and PV include hydroxyurea, long-acting interferons, anagrelide in ET, and ruxolitinib in PV. Selecting the ideal agent requires careful consideration of the toxicity profiles and individual treatment goals. In this review the existing literature on cytoreductive decisions in ET and PV is summarized, with an emphasis on risk-stratification, highlighting the need for personalized care in order to maximize the benefit of these therapies while minimizing toxicities.
Topics: Humans; Polycythemia Vera; Thrombocythemia, Essential; Cytoreduction Surgical Procedures; Hydroxyurea; Thrombosis
PubMed: 38066871
DOI: 10.1182/hematology.2023000451 -
Neurological Research Dec 2023In polycythemia vera (PV) patients undergoing phlebotomy, iron deficiency (ID) may develop. ID has been linked to restless legs syndrome (RLS), and in one study, 29.6%...
INTRODUCTION
In polycythemia vera (PV) patients undergoing phlebotomy, iron deficiency (ID) may develop. ID has been linked to restless legs syndrome (RLS), and in one study, 29.6% of PV patients had RLS. We aimed to evaluate the frequency of RLS in PV and to evaluate factors that might play a role in RLS development among PV and essential thrombocythemia (ET) patients.
METHODS
We consecutively included PV cases as the patient group, and ET and ID patients and healthy subjects (HSs) were included as controls. Those with conditions that could lead to RLS were excluded. All subjects were questioned according to the diagnostic criteria of the International Restless Legs Syndrome Study Group.
RESULTS
Twenty-seven PV, 23 ET, and 22 ID patients and 23 HSs were included. RLS was detected in 25.9%, 34.8%, and 45.5% of PV, ET, and ID patients, respectively. None of the HSs had RLS. In univariate analysis, interferon-α and anagrelide use, magnesium levels, and the Leeds assessment of neuropathic symptoms and signs (LANSS) scores had a significant impact on RLS in PV and ET patients ( = 0.014, = 0.032, = 0.036, and = 0.003, respectively).
CONCLUSION
RLS was more common among PV and ET patients than HSs, which was irrespective to the iron status. RLS was more frequent in ET patients than that observed in PV cases, indicating that ID may not be the only causative factor for RLS development in PV. Further prospective studies are needed to determine the prevalence and risk factors of RLS developing in PV and ET.
Topics: Humans; Polycythemia Vera; Cross-Sectional Studies; Restless Legs Syndrome; Iron Deficiencies; Prevalence
PubMed: 37736879
DOI: 10.1080/01616412.2023.2257443 -
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 -
American Journal of Health-system... Nov 2023This article concisely evaluates current therapies that have received regulatory approval for the treatment of classic myeloproliferative neoplasms (MPNs). Pertinent...
PURPOSE
This article concisely evaluates current therapies that have received regulatory approval for the treatment of classic myeloproliferative neoplasms (MPNs). Pertinent pathophysiology and supportive care are discussed. Emerging therapies are also briefly described.
SUMMARY
MPNs are a heterogeneous group of diseases characterized by acquired abnormalities of hematopoietic stem cells (HSCs), resulting in the generation of transformed myeloid progenitor cells that overproduce mature and immature cells within the myeloid lineage. Mutations in JAK2 and other driver oncogenes are central to the genetic variability of these diseases. Cytoreductive therapies such as hydroxyurea, anagrelide, interferon, and therapeutic phlebotomy aim to lower the risk of thrombotic events without exposing patients to an increased risk of leukemic transformation. However, no comparisons can be made between these therapies, as reduction of thrombotic risk has not been used as an endpoint. On the other hand, Janus kinase (JAK) inhibitors such as ruxolitinib, fedratinib, pacritinib, and momelotinib (an investigational agent at the time of writing) directly target the constitutively activated JAK-signal transducer and activator of transcription (JAK-STAT) pathway of HSCs in the bone marrow. Mutations of genes in the JAK-STAT signaling pathway provide a unifying understanding of MPNs, spur therapeutic innovations, and represent opportunities for pharmacists to optimize mitigation strategies for both disease-related and treatment-related adverse effects.
CONCLUSION
Treatment options for MPNs span a wide range of disease mechanisms. The growth of targeted therapies holds promise for expanding the treatment arsenal for these rare, yet complex diseases and creates opportunities to optimize supportive care for affected patients.
Topics: Humans; Neoplasms; Myeloproliferative Disorders; Bone Marrow; Signal Transduction; Protein Kinase Inhibitors
PubMed: 37556726
DOI: 10.1093/ajhp/zxad181