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Current Hematologic Malignancy Reports Oct 2016Anagrelide (ANA) is a drug with specific platelet-lowering activity, used primarily in ET, registered as a second-line drug in essential thrombocythemia (ET) in Europe... (Review)
Review
Anagrelide (ANA) is a drug with specific platelet-lowering activity, used primarily in ET, registered as a second-line drug in essential thrombocythemia (ET) in Europe and in some countries as first-line therapy, in USA licensed by FDA for thrombocythemia in myeloproliferative neoplasms (MPN). The platelet-lowering efficacy is similar to that of hydroxycarbamide (HC), around 70 % complete response and 90 % partial response. Side effects are common, especially headache and tachycardia, but usually subside or disappear within a few weeks. Around 20 % of patients stop ANA therapy due to side effects or insufficient response. Studies of treatment patterns in Europe show that ANA is preferentially given to younger patients, probably because of the concern for a possible leukemogenic effect of the common first-line drug, HC. Only two randomized studies have compared the efficacy of ANA and HC in preventing thrombosis and haemorrhage, the larger of them showing a slightly better efficacy of HC, the other showing non-inferiority of ANA to HC. A recent observational 5-year study of 3600 patients shows a low and basically similar efficacy of ANA and other cytoreductive therapies in ET. ANA does not appear to inhibit fibrosis development, and probably due to its anticoagulation properties, the combination of ASA and ANA produces an increased rate of haemorrhage. Combination of ANA with HC or interferon (IFN) is feasible and effective in patients with insufficient platelet response to mono-therapy.
Topics: Age Factors; Bone Marrow; Cardiovascular Diseases; Humans; Interferon-alpha; Myeloproliferative Disorders; Platelet Aggregation Inhibitors; Quinazolines; Tachycardia; Thrombocythemia, Essential
PubMed: 27497846
DOI: 10.1007/s11899-016-0335-0 -
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 -
Pharmacological Research Feb 2018Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as... (Review)
Review
Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascular diseases. Mutational activation of JAKs is also responsible for several haematological malignancies, including myeloproliferative neoplasms and acute lymphoblastic leukaemia. Accumulating evidence links adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), an energy sensor and regulator of organismal and cellular metabolism, with the suppression of immune and inflammatory processes. Recent studies have shown that activation of AMPK can limit JAK-STAT-dependent signalling pathways via several mechanisms. These novel findings support AMPK activation as a strategy for management of an array of disorders characterised by hyper-activation of the JAK-STAT pathway. This review discusses the pivotal role of JAK-STAT signalling in a range of disorders and how both established clinically used and novel AMPK activators might be used to treat these conditions.
Topics: AMP-Activated Protein Kinases; Animals; Humans; Inflammation; Interleukin-6; Janus Kinases; STAT Transcription Factors; Signal Transduction
PubMed: 29037480
DOI: 10.1016/j.phrs.2017.10.001 -
Cureus Mar 2021Treatment modalities for polycythemia vera (PV) have evolved over time. Phlebotomy and low-dose aspirin suffice in low-risk patients, but cytoreductive therapies are... (Review)
Review
Treatment modalities for polycythemia vera (PV) have evolved over time. Phlebotomy and low-dose aspirin suffice in low-risk patients, but cytoreductive therapies are indicated in all high-risk patients (age ≥ 65 years or those with a history of PV-related thrombotic event) and may be considered for low-risk patients with progressively increasing splenomegaly, progressively increasing leucocyte and platelet counts, and for those who do not tolerate phlebotomy. Hydroxyurea/hydroxycarbamide or interferons can be used as first-line drugs. Hydroxyurea may not be tolerated by some patients, and it also carries risk of myelosuppression. Interferon alfa is especially useful for PV symptoms, and the newer preparation, ropeginterferon alfa-2b, has lesser incidence of flu-like reactions. Ruxolitinib reduces the JAK2V617F mutation burden and is used as a second-line drug. Anagrelide reduces platelet production and can be used in conjunction with hydroxyurea in patients with excessive thrombocytosis. The alkylating agent, busulfan, can also be used as a last resort in patients with a limited life expectancy. Prospective future treatments include givinostat, a histone deacetylase inhibitor, and idasanutlin, a murine double minute 2 antagonist.
PubMed: 33936902
DOI: 10.7759/cureus.14193 -
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 -
International Journal of Hematology Aug 2016Anagrelide is a treatment option for patients with essential thrombocythemia. Although the clinical efficacy of anagrelide has been established, there is limited...
Anagrelide is a treatment option for patients with essential thrombocythemia. Although the clinical efficacy of anagrelide has been established, there is limited knowledge of the molecular mechanism underlying its effect. Here, we evaluated the effect of anagrelide on primary megakaryocytic progenitors from cord blood-derived CD34-positive cells. Anagrelide treatment reduced the expression of megakaryocytic markers (CD41 and CD61). Microarray analysis was performed to characterize gene profiles altered by exposure to anagrelide. The analysis demonstrated upregulation and downregulation (>2-fold) of eight and 34 genes, respectively, in anagrelide-treated megakaryocyte progenitors. This included genes encoding prototypical megakaryocytic proteins, such as PPBP, PF4, and GP6. Gene ontology analysis of genes suppressed by anagrelide treatment revealed significant enrichment of genes involved in platelet activation and degranulation. Expression levels of transcription factors involved in megakaryocyte commitment/differentiation were further evaluated by quantitative RT-PCR, demonstrating significant downregulation of FLI1 and TAL1 in anagrelide-treated megakaryocyte progenitors. Knockdown of TAL1 in primary megakaryocyte progenitors confirmed significant downregulation of FLI1 and megakaryocytic genes. Anagrelide had no significant effect on the surface expression of erythroid markers or on the expression of transcription factors involved in erythroid commitment/differentiation. In conclusion, anagrelide suppresses megakaryocytic differentiation, partly through decreasing the expression of megakaryocytic transcription factors.
Topics: Cell Differentiation; Cells, Cultured; Fetal Blood; Gene Expression Profiling; Humans; Megakaryocyte Progenitor Cells; Megakaryocytes; Platelet Aggregation Inhibitors; Quinazolines; Transcription Factors
PubMed: 27084257
DOI: 10.1007/s12185-016-2006-2 -
Blood Cancer Journal Nov 2015Polycythemia vera (PV) and essential thrombocythemia (ET) constitute two of the three BCR-ABL1-negative myeloproliferative neoplasms and are characterized by relatively... (Review)
Review
Polycythemia vera (PV) and essential thrombocythemia (ET) constitute two of the three BCR-ABL1-negative myeloproliferative neoplasms and are characterized by relatively long median survivals (approximately 14 and 20 years, respectively). Potentially fatal disease complications in PV and ET include disease transformation into myelofibrosis (MF) or acute myeloid leukemia (AML). The range of reported frequencies for post-PV MF were 4.9-6% at 10 years and 6-14% at 15 years and for post-ET MF were 0.8-4.9% at 10 years and 4-11% at 15 years. The corresponding figures for post-PV AML were 2.3-14.4% at 10 years and 5.5-18.7% at 15 years and for post-ET AML were 0.7-3% at 10 years and 2.1-5.3% at 15 years. Risk factors cited for post-PV MF include advanced age, leukocytosis, reticulin fibrosis, splenomegaly and JAK2V617F allele burden and for post-ET MF include advanced age, leukocytosis, anemia, reticulin fibrosis, absence of JAK2V617F, use of anagrelide and presence of ASXL1 mutation. Risk factors for post-PV AML include advanced age, leukocytosis, reticulin fibrosis, splenomegaly, abnormal karyotype, TP53 or RUNX1 mutations as well as use of pipobroman, radiophosphorus (P(32)) and busulfan and for post-ET AML include advanced age, leukocytosis, anemia, extreme thrombocytosis, thrombosis, reticulin fibrosis, TP53 or RUNX1 mutations. It is important to note that some of the aforementioned incidence figures and risk factor determinations are probably inaccurate and at times conflicting because of the retrospective nature of studies and the inadvertent labeling, in some studies, of patients with prefibrotic primary MF or 'masked' PV, as ET. Ultimately, transformation of MPN leads to poor outcomes and management remains challenging. Further understanding of the molecular events leading to disease transformation is being investigated.
Topics: Fusion Proteins, bcr-abl; Humans; Leukemia, Myeloid, Acute; Lymphocyte Activation; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential
PubMed: 26565403
DOI: 10.1038/bcj.2015.95 -
Journal of Thrombosis and Thrombolysis Nov 2015Cytoreductive therapy, with or without low-dose aspirin, is the mainstay of thrombotic risk reduction in patients with essential thrombocythemia (ET), but the optimal... (Comparative Study)
Comparative Study Meta-Analysis Review
Cytoreductive therapy, with or without low-dose aspirin, is the mainstay of thrombotic risk reduction in patients with essential thrombocythemia (ET), but the optimal choice of agent remains unclear. The aim of this study was to meta-analyze currently available data comparing anagrelide to hydroxyurea for reduction of rates of thrombosis, bleeding and death among patients with ET. A literature search for randomized, controlled trials comparing anagrelide to hydroxyurea among patients with ET revealed two published studies. Statistical analysis was performed using fixed effects meta-analysis. Rates of thrombosis were similar between patients treated with hydroxyurea vs anagrelide (RR 0.86, 95 % CI 0.64-1.16). Rates of major bleeding were lower in patients treated with hydroxyurea (RR 0.37, 95 % CI 0.18-0.75). Rates of progression to acute myeloid leukemia were not statistically different (RR 1.50, 95 % CI 0.43-5.29). The composite of thrombosis, major bleeding and death favored hydroxyurea (RR 0.78, 95 % CI 0.63-0.97). In conclusion, our analysis supports use of hydroxyurea as a first-line cytoreductive agent for patients with ET, based largely on decreased rates of major bleeding. Anagrelide appears to be equally effective for protection against thrombotic events and may be an appropriate alternative for patients who are intolerant of hydroxyurea.
Topics: Hemorrhage; Humans; Hydroxyurea; Quinazolines; Thrombocythemia, Essential; Thrombosis
PubMed: 25894476
DOI: 10.1007/s11239-015-1218-2 -
Wiener Klinische Wochenschrift Jan 2021According to the World Health Organization (WHO) classification, essential (primary) thrombocythemia (ET) is one of several Bcr-Abl negative chronic myeloproliferative...
According to the World Health Organization (WHO) classification, essential (primary) thrombocythemia (ET) is one of several Bcr-Abl negative chronic myeloproliferative neoplasms (MPN). The classical term MPN covers the subcategories of MPN: ET, polycythemia vera (PV), primary myelofibrosis (PMF), and prefibrotic PMF (pPMF). ET is marked by clonal proliferation of hematopoietic stem cells, leading to a chronic overproduction of platelets. At the molecular level a JAK2 (Janus Kinase 2), calreticulin, or MPL mutation is found in the majority of patients. Typical ongoing complications of the disease include thrombosis and hemorrhage. Primary and secondary prevention of these complications can be achieved with platelet function inhibitors and various cytoreductive drugs including anagrelide, hydroxyurea and interferon. After a long follow up, in a minority of ET patients the disease transforms into post-ET myelofibrosis or secondary leukemia. Overall, life expectancy with ET is only slightly decreased.
Topics: Austria; Humans; Mutation; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential
PubMed: 33215234
DOI: 10.1007/s00508-020-01761-3 -
Future Oncology (London, England) Dec 2014Essential thrombocythemia patients develop acute myeloid leukemia (AML) at a rate of 1-4% during a median follow-up of 7-10 years. The risk increases with advanced age,...
Essential thrombocythemia patients develop acute myeloid leukemia (AML) at a rate of 1-4% during a median follow-up of 7-10 years. The risk increases with advanced age, anemia, platelet count ≥ 1000 × 10(9)/l, the presence of ≥ 2 somatic mutations and after the first decade of diagnosis. The use of alkylating agents and (32)radiophosphorus, particularly in higher doses, but not hydroxyurea and anagrelide, increases the risk. AML in essential thrombocythemia patients is frequently associated with unfavorable cytogenetics and poor prognosis. In young and fit patients, AML-type induction chemotherapy followed by allogeneic stem cell transplantation may offer the best chance of long-term disease control. In select elderly patients with poor performance status, hypomethylating agent such as azacytidine may prolong survival.
Topics: Azacitidine; Cell Transformation, Neoplastic; Humans; Janus Kinase 2; Leukemia, Myeloid, Acute; Mutation; Prognosis; Risk Factors; Stem Cell Transplantation; Thrombocythemia, Essential; Transplantation, Homologous
PubMed: 25531047
DOI: 10.2217/fon.14.239