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Background and Objectives: 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. Materials and Methods: 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. Results: The median age was 62 years old (range, 26–87) and median platelet count was 912 × 109/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%, p = 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 (p = 0.008 for HU monotherapy vs. combination therapy and p < 0.01 for AG monotherapy vs. combination therapy). Conclusions: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

As the discussion of first-line anagrelide treatment is ongoing, we aimed to prospectively examine the efficacy and safety of anagrelide in cytoreduction therapy-naïve high risk essential thrombocythemia (ET) patients in Korea. Seventy patients from 12 centers were treated with anagrelide monotherapy for up to 8 weeks, followed up until 24 months. At week 8, 50.0% of the patients were able to achieve platelet < 600 x 109/L, and by 12 months, 55/70 (78.6%) patients stayed on anagrelide, and 40.0% patients showed platelet normalization. 14 patients required additional hydroxyurea (HU) for cytoreduction. The median daily dose of needed HU was 500mg (range 250mg -- 1500mg). The efficacy was independent of the somatic mutation status. There were 4 thromboembolic events and 7 bleeding events during the follow-up period. The most common adverse events associated with anagrelide use were headache, followed by palpitation/chest discomfort, edema and generalized weakness/fatigue. 7 patients wished to discontinue anagrelide treatment due to adverse events (3 due to headache; 2 due to edema; 1 due to palpitation and 1 due to skin eruption). All in all, first-line anagrelide treatment showed a favorable response with tolerable safety profiles regardless of somatic mutation status. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

As the discussion of first-line anagrelide treatment is ongoing, we aimed to prospectively examine the efficacy and safety of anagrelide in cytoreduction therapy-naïve high risk essential thrombocythemia (ET) patients in Korea. Seventy patients from 12 centers were treated with anagrelide monotherapy for up to 8 weeks, followed up until 24 months. At week 8, 50.0% of the patients were able to achieve platelet < 600 x 109/L, and by 12 months, 55/70 (78.6%) patients stayed on anagrelide, and 40.0% patients showed platelet normalization. 14 patients required additional hydroxyurea (HU) for cytoreduction. The median daily dose of needed HU was 500mg (range 250mg – 1500mg). The efficacy was independent of the somatic mutation status. There were 4 thromboembolic events and 7 bleeding events during the follow-up period. The most common adverse events associated with anagrelide use were headache, followed by palpitation/chest discomfort, edema and generalized weakness/fatigue. 7 patients wished to discontinue anagrelide treatment due to adverse events (3 due to headache; 2 due to edema; 1 due to palpitation and 1 due to skin eruption). All in all, first-line anagrelide treatment showed a favorable response with tolerable safety profiles regardless of somatic mutation status.

Background/Aim: This work aimed to prospectively evaluate the clinical significance of circulating microparticles (MPs) in relation to thrombotic risk factors and thrombotic complications in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN). Patients and Methods: In a cohort of 206 patients with MPN, MPs’ procoagulant activity was measured by the Zymuphen functional assay in 429 samples, while plateletand erythrocyte-MPs were enumerated by flow cytometry in 558 samples. Results: MPN patients had higher MP levels than the control group. The levels of MPs were higher in male patients, smokers, and those who were older than 60 years, and in the presence of JAK2V617F mutation, history of thrombosis, platelets >400×109/l, hematocrit >45%, or leukocytes >10×109/l. Cytoreductive treatment reduced MP levels, with anagrelide being associated with lower MP levels than hydroxyurea. Conclusion: The relationship with thrombotic risk factors indicates a possible role of MPs in the complex thrombotic mechanism, though cytoreductive treatment seems to affect this role through reducing MP levels. [ABSTRACT FROM AUTHOR]

A simple and selective method for liquid chromatography has been developed to determine the degradation impurities in solid oral dosage forms of Anagrelide (Antithrombocythemic agent). An excellent resolution between Anagrelide (ANG) and its related substances was achieved with Symmetry C8, 250 mm × 4.6 mm, 3.0 μm column. and mobile phase A (phosphate buffer, pH 4.1) and mobile phase B (the mixture of acetonitrile, methanol, and buffer in the ratio of 40:40:20 v/v/v). The column oven temperature was maintained at 40°C. The flow rate was fixed at 0.8 mL/min, and elution was monitored at 254 nm using a UV detector. The method was validated for precision, accuracy, specificity, linearity, and sensitivity. The validation studies demonstrated that the current HPLC method is reproducible, specific and accurate for its intended purpose. Linearity was observed for ANG, and its impurities are more than (R2 > 0.995). The limit of detection and limit of quantitation (LOQ) was found to be adequate (< 0.05 %) for the estimation of impurities. The RSD for intra- day and inter-day precision was found to be between 0.5 % to 2.5 %. The percentage of recovery was found between 95 % to 105 %. Forced degradation studies were performed on ANG under different conditions such as acidic, basic, oxidation, photostability, and thermal degradation. Based on the results, this is found to be simple, specific, precise, accurate, linear, and stability-indicating method. Hence it can be used to determine the Anagrelide-related impurities in the capsule dosage form. It is economically feasible and user-friendly method. The proposed method was successfully applied in quality control labs for stability analysis. [ABSTRACT FROM AUTHOR]

Abstract Background Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by thrombocytosis and a propensity for both thrombotic and hemorrhagic events. ET rarely occurs simultaneously with colorectal cancer. Here, we report a case of colorectal cancer in an ET patient treated using laparoscopic ileocecal resection. Case presentation A 40-year-old woman was admitted to our hospital after presenting with liver dysfunction. She had been previously diagnosed with ET; aspirin and anagrelide had been prescribed. Subsequent examination at our hospital revealed cecal cancer. Distant metastasis was absent; laparoscopic ileocecal resection was performed. Anagrelide was discontinued only on the surgery day. She was discharged on the seventh postoperative day without thrombosis or hemorrhage. However, when capecitabine and oxaliplatin were administered as adjuvant chemotherapy with continued anagrelide administration, she experienced hepatic dysfunction and thrombocytopenia; thus, anagrelide was discontinued. Five days later, her platelet count recovered. Subsequently, anagrelide and aspirin administration was resumed, without any adjuvant chemotherapy. Her liver function normalized gradually in 4 months. One-year post operation, she is well without tumor recurrence or new metastasis. Conclusions To our knowledge, this is the first report of laparoscopic colectomy performed on an ET patient receiving anagrelide. Our report shows that complications such as bleeding or thrombosis can be avoided by anagrelide administration. Contrastingly, thrombocytopenia due to anagrelide intake should be considered when chemotherapy that could cause bone marrow suppression is administered.

Background and Purpose: When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few articles have been published about the effects of hydroxycarbamide (hydroxyurea, HU) and anagrelide (ANA) on renal function in ET patients. This study is the largest analysis of nephrotoxicity of cytoreductive drugs used in ET therapy so far, which additionally includes risk factors for the progression of kidney disease and coexisting genetic mutation. Experimental Approach: The retrospective study included 310 patients diagnosed with ET. Demographic data, comorbidities, Cr, and estimated glomerular filtration rate (eGFR) were all taken into account prior to diagnosis and after 6 months of HU and ANA treatment. Key Results: A statistically significant difference was found between Cr and eGFR levels at baseline and after 6 months of treatment (p < 0.001). The applied treatment (HU and ANA) had the greatest impact on kidney function. ANA significantly increased the risk of worsening renal function in contrary to hydroxycarbamide after 6 months of treatment (eGFR change: median +1 mL/min/1.73 m2 [interquartile range (IQR) (−4)–(+7)] in the HU group vss. median −13 mL/min/1.73 m2 [IQR (−18)–(−6)] in the ANA group, odds ratio [OR] 7.92 95% confidence interval [95% CI] [4.17–15.08], p < 0.001). Lowering of eGFR <60 mL/min/1.73 m2 occurred in 31 patients (31.0%) from the ANA group and 10 people (4.8%) treated with HU (p = 0.000). In 1 patient from the ANA group, >50% decrease in eGFR was observed. The chance for an increase in Cr levels was higher in people with pre-existing arterial hypertension (OR 1.92 CI = 95% [1.21–3.05], p = 0.006). Sex, type of mutation found (JAK2 V617F or CALR), and previous renal impairment did not affect renal function after 6 months of treatment. In addition, there was no difference in the efficacy of ET treatment between HU and ANA (p = 0.998). Conclusions and Implications: The observations indicate that ANA should be used in patients with ET with great caution and taking into account the risk of worsened kidney function. [ABSTRACT FROM AUTHOR]

Essential thrombocythaemia (ET) is a rare myeloproliferative neoplasm. This multicentre, Phase 3b, randomised, open-label, non-inferiority study investigated the cardiac safety, efficacy and tolerability of first-line treatment with anagrelide or hydroxyurea in high-risk ET patients for up to 3 years. Eligible patients aged ≥ 18 years with a diagnosis of high-risk ET confirmed by bone marrow biopsy within 6 months of randomisation received anagrelide (n = 75) or hydroxyurea (n = 74), administered twice daily. Treatment dose for either compound was titrated to the lowest dose needed to achieve a response. Planned primary outcome measures were change in left ventricular ejection fraction from baseline over time and platelet count at Month 6. Planned secondary outcome measures were platelet count change from baseline at Months 3 and 36; percentage of patients with complete or partial response; time to complete or partial response; number of patients with thrombohaemorrhagic events; and changes in white blood cell count or red blood cell count over time. Neither treatment altered cardiac function. There were no significant differences in adverse events between treatment groups, and no reports of malignant transformation. The incidence of disease-related thrombotic or haemorrhagic events was numerically higher in anagrelide-treated patients. Both treatments controlled platelet counts at 6 months, with the majority of patients experiencing complete or partial responses. In conclusion, these results suggest that long-term treatment with anagrelide is not associated with adverse effects on cardiac function. This is one of the few studies using left ventricular ejection fraction assessment and central biopsy reading to confirm the diagnosis of ET. Trial registration number: Clinicaltrials.gov NCT00202644 [ABSTRACT FROM AUTHOR]

Abstract Background Patients with polycythemia vera (PV) have a higher mortality risk compared with the general population, primarily driven by cardiovascular disease, thrombotic events (TEs), and hematologic transformations. The goal of risk-adapted therapy in PV is prevention of TEs. Current treatment recommendations indicate that high-risk patients (aged ≥ 60 years and/or with history of TEs) should be managed with cytoreductive medications, phlebotomy, and low-dose aspirin. This noninterventional study was conducted to describe real-world cytoreductive medication treatment in adult patients with PV, stratified by risk, in the United States. Methods This retrospective analysis used claims data from the Truven Health MarketScan® database. Inclusion criteria were ≥ 2 nondiagnostic claims for PV ≥ 30 days apart, age ≥ 18 years, continuous enrollment during the preindex period (January 1 to December 31, 2012), and continuous enrollment or death during the postindex period (January 1, 2013, to December 31, 2014). Assessments included patient demographics, clinical characteristics, and treatment with cytoreductive medications. Results A total of 2856 patients were identified for this analysis, including 1823 with high-risk PV and 1033 with low-risk PV. Mean (SD) age was 62.5 (13.5) years, and 65.9% of patients were male. Preindex comorbid conditions of interest were more common in high-risk than low-risk patients, including hypertension (65.0% vs 43.1%), type 2 diabetes (21.7% vs 10.1%), and congestive heart failure (6.6% vs 0.6%). Among patients who received preindex cytoreductive therapy, the most commonly used medications in high-risk (n = 666) and low-risk (n = 160) patients were hydroxyurea (94.7 and 87.5%, respectively), anagrelide (7.4 and 11.9%), and interferon (1.7 and 4.4%). Among patients who initiated cytoreductive therapy postindex, the most commonly used medications in high-risk (n = 100) and low-risk (n = 35) patients were hydroxyurea (97.0 and 91.4%, respectively), anagrelide (4.0 and 2.9%), and interferon (2.0 and 8.6%). Overall, 42.0% of high-risk and 18.9% of low-risk patients received cytoreductive medication during the preindex or postindex periods. Conclusions Despite consistent guideline recommendations for cytoreductive therapy in patients with high-risk PV, this analysis revealed that only a minority of these patients received cytoreductive medication. A notable proportion of high-risk patients with PV would likely benefit from a revised treatment plan that aligns with current guidelines.

Introduction: Real-world data of responses, quality-of-life (QOL) changes and adverse events in patients with myeloproliferative neoplasms (MPN) on conventional therapy (hydroxyurea ± anagrelide), pegylated interferon alpha-2A (PEG-IFNα-2A) or ruxolitinib are limited. Methods: We prospectively studied MPN patients receiving conventional therapy, PEG-IFNα-2A or ruxolitinib. Next-generation sequencing of 69 myeloid-related genes was performed. Clinicohematologic responses, adverse events, and QOL (determined by the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score, MPN-SAF TSS) were evaluated. Results: Seventy men and fifty-five women with polycythemia vera (PV) (N = 23), essential thrombocythemia (ET) (N = 56) and myelofibrosis (MF) (N = 46) were studied for a median of 36 (range: 19–42) months. In PV, responses were comparable for different modalities. CREBBP mutations were associated with inferior responses. In ET, PEG-IFNα-2A resulted in superior clinicohematologic complete responses (CHCR) (P = 0.045). In MF, superior overall response rates (ORR) were associated with ruxolintib (P = 0.018) and JAK2V617F mutation (P = 0.04). For the whole cohort, ruxolitinib led to rapid and sustained reduction in spleen size within the first 6 months, and significant improvement of QOL as reflected by reduction in MPN-SAF TSS (P < 0.001). Adverse events of grades 1–2 were observed in 44%, 62% and 20% of patients receiving conventional therapy, PEG-IFNα-2A and ruxolitinib respectively; and of grade 3–4 in 7% and 9% of patients receiving PEG-IFNα-2A and ruxolitinib. Conclusions: Conventional therapy, PEG-IFNα-2A and ruxolitinib induced responses in all MPN subtypes. PEG-IFNα-2A led to superior CHCR in ET; whereas ruxolitinib resulted in superior ORR in MF, and significant reduction in spleen size and improvement in QOL. [ABSTRACT FROM AUTHOR]

Objective: We report an extension study of patients with essential thrombocythaemia (ET) in the Hungarian Myeloproliferative Neoplasm (HUMYPRON) Registry, which demonstrated that over 6 years anagrelide significantly decreased the number of patients experiencing minor arterial and minor venous thrombotic events (TEs) vs hydroxyurea+aspirin. Methods: Data on patients with ET were collected through completion of a questionnaire developed according to 2008 WHO diagnostic criteria and with regard to Landolfi, Tefferi and IPSET criteria for thrombotic risk. Data were entered into the registry from 14 haematological centres. TEs, secondary malignancies, disease progression and survival were compared between patients with ET treated with anagrelide (n = 116) and with hydroxyurea+aspirin (n = 121). Results: Patients were followed for (median) 10 years. A between‐group difference in the number of patients with TEs was observed (25.9% anagrelide vs 38.0% hydroxyurea+aspirin; P =.052). Minor arterial events were more frequently reported in the hydroxyurea+aspirin group (P <.001); there were marginally more reports of major arterial events in the anagrelide group (P =.049). TE prior to diagnosis was found to significantly influence TE incidence (P >.001). Progression‐free survival (P =.004) and survival (P =.001) were significantly increased for the anagrelide group vs hydroxyurea+aspirin. Conclusions: Anagrelide reduced TEs, and increased progression‐free and overall survival vs hydroxyurea+aspirin over (median) 10 years. [ABSTRACT FROM AUTHOR]

Background and aims: Anagrelide is a drug effective in reducing platelet counts in essential thrombocythemia (ET) and Ph1‐negative myeloproliferative neoplasms. The aim of this study was to evaluate the real‐life use of anagrelide in patients with ET followed over 25 years at the Haematological Institutes belonging to "Ph1‐negative Myeloproliferative Neoplasms Latium Group." Patients and methods: Eligibility criteria were diagnosis of ET and treatment with anagrelide. Data were collected through an ad hoc case report form. Results: One hundred and fifty patients received anagrelide for a median time of 7.4 years (0.1‐23.2). Anagrelide was administered as first‐line therapy in 34.7% of patients, as second‐line in 52% and as third‐line in 13.3%: 85.4% responded to therapy. Sixty‐eight/136 evaluable patients reported side effects: palpitations, peripheral vasodilation, anaemia, diarrhoea and gastric distress. Fourteen thrombotic (arterial 10, venous 4) and 51 bleeding events (minor 48, major 3) occurred. Sixteen/150 (10.6%) patients developed secondary myelofibrosis and 3/150 (2%) an acute myeloid leukaemia. Conclusions: In our experience, anagrelide is an effective drug in reducing platelet levels in a high percentage of patients with ET. It is especially addressed to younger people. A careful assessment of the thrombotic risk and monitoring of cardiac function, at diagnosis and during follow‐up, is mandatory. [ABSTRACT FROM AUTHOR]

Anagrelide is widely used for cytoreductive therapy in patients with essential thrombocythemia who are at high risk for thrombosis. The recommended starting dose in the package insert of anagrelide varies by country. A high starting dose leads to an early onset of action, but causes a higher incidence of adverse events. This relationship indicates that both the onset of action and side effects of anagrelide are dose dependent. We retrospectively compared the efficacy and safety of anagrelide as a first-line drug between patients with essential thrombocythemia who started at 0.5 or 1.0 mg/day. Incidence of total adverse events and anagrelide-related palpitation, discontinuation rates, and the median daily dose of anagrelide were lower in the 0.5 mg/day group than in the 1.0 mg/day group; however, comparable platelet-lowering effects were achieved in both groups. These data suggest that a low starting dose of anagrelide followed by dose escalation may result in fewer adverse events and lower discontinuation rates, while providing desirable platelet-lowering effects. Initiating anagrelide at a lower dose may be a useful approach in actual clinical practice. [ABSTRACT FROM AUTHOR]

Herein we report the case of a girl with association of Budd-Chiari syndrome (BCS), essential thrombocythaemia (ET), and celiac disease (CD). To our knowledge, this is one out of eight cases in the literature of BCS complicated with CD, and the only one complicated with ET. This case is particularly significant because anagrelide therapy was started at an unusually early age. A four-year-old girl with ET treated with anagrelide was admitted to our hospital with suspicion of BCS. Ultrasound colour Doppler and computed tomography imaging revealed enlargement of the caudate lobe, splenomegaly, accessory hepatic veins, umbilical vein recanalisation, and ascites. The diagnosis of the CD was confirmed by serology (EmA IgA 1 : 800, tTG IgA > 130 U/ml). Two years later Duhring's disease was confirmed histologically with recovery after diet modification. Four years later she is still being treated with anagrelide, anticoagulant drugs and is on a well-controlled gluten-free diet. [ABSTRACT FROM AUTHOR]

Background: JAK2 V617F mutation increases the risk of thrombosis, and both ischemic and hemorrhagic strokes can occur in essential thrombocythemia (ET). The mechanisms underlying ischemic stroke in ET are diverse, and hemorrhagic stroke has rarely been reported in ET. Methods: Among 627 stroke patients, those identified as having ET were investigated retrospectively. A comprehensive systemic literature search of the PubMed database was also conducted. Results: Two cases were extracted with the diagnosis of ET who developed SAH and then ischemic stroke. In Case 1, a 47-year-old woman developed SAH in the left high convexity. Eleven hours later, acute cerebellar infarction suddenly developed due to right vertebral artery dissection. In Case 2, a 70-year-old woman developed SAH in the right high convexity. Magnetic resonance angiography showed multifocal stenotic changes in intracranial arteries. Three days later, she developed acute brain infarcts in the right middle cerebral artery territory. Eight weeks later, multifocal stenotic lesions improved. The literature review revealed 5 patients with hemorrhagic stroke and 40 patients with ischemic stroke associated with ET. Age at onset varied, female gender predominated, and the frequency of JAK2 V617F mutation was high. Atherosclerotic vascular risk factors were more common in ischemic stroke, but not in hemorrhagic stroke. Conclusions: The current study describes rare cases of SAH accompanied by ischemic stroke secondary to ET along with a review of the current literature, implying specific mechanisms for cerebral artery disorders associated with JAK2 V617F mutation. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy‐naïve essential thrombocythemia (ET) patients in a real‐world setting. Method: Data from 53 ET patients who received anagrelide as a first‐line therapy were reviewed for patient characteristics, antiplatelet status, cytoreduction status, therapeutic effects, adverse events, thrombohemorrhagic event development, progression to myelofibrosis or acute leukemia, and cause of death. Results: The rate of achieving a platelet count of <600 × 109/L during anagrelide monotherapy was 83.0%. Adverse events occurred in 32 of 53 patients, and tended to be slightly more severe in patients with cardiac failure; however, they were mostly tolerable. The therapeutic effect of anagrelide was consistent, regardless of genetic mutation profiles. The incidence of anemia as an adverse event was significantly higher in the CALR mutation‐positive group. Favorable platelet counts were also achieved in patients for whom hydroxyurea was introduced as a replacement for anagrelide or in addition to anagrelide because of unresponsiveness or intolerance to treatment. Conclusion: In Japanese cytoreduction therapy‐naïve ET patients, anagrelide administration as a first‐line therapy demonstrated favorable effects in reducing platelet counts, and its safety profile that was generally consistent with those in previous reports. [ABSTRACT FROM AUTHOR]

Summary: Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing frequency and improving tolerability, without diminishing efficacy. This multicentre, randomized, double blind, active‐controlled, non‐inferiority trial investigated the efficacy, safety and tolerability of anagrelide prolonged release (A‐PR) over a reference product in high‐risk ET patients, either anagrelide‐naïve or ‐experienced. In a 6 to 12‐week titration period the individual dose for the consecutive 4‐week maintenance period was identified. The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, 28). Of 112 included patients 106 were randomized. The mean screening platelet counts were 822 × 109/l (95% confidence interval (CI) 707–936 × 109/l) and 797 × 109/l (95% CI 708–883 × 109/l) for A‐PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 109/l for A‐PR (95% CI 254–311) and 305 × 109/l (95% CI 276–337) for the reference product (P < 0·0001, for non‐inferiority). Safety and tolerability were comparable between both drugs. The novel prolonged‐release formulation was equally effective and well tolerated compared to the reference product. A‐PR provides a more convenient dosing schedule and will offer an alternative to licensed immediate‐release anagrelide formulations. [ABSTRACT FROM AUTHOR]

Ischaemia–reperfusion injury (IRI) has been a major challenge during acute coronary syndrome (ACS) with reperfusion therapy. But despite consistent therapeutic improvements in terms of optimized reperfusion strategies and novel antithrombotic medications, IRI still remains highly prevalent. Platelets play a pivotal role in the IRI. Expression of reticulated platelets (RPs), is found among patients with ACS, which is associated with increased activity and contributes to an impaired response to antiplatelet drugs. RPs might play a more important role in IRI than mature platelets, regarded as a potential therapeutic target for myocardial IRI. Anagrelide, an antithrombopoietic drug indicating for essential thrombocythemia, decreases newly formed platelets by inhibiting the proliferation and differentiation of megakaryocytes in bone marrow. We hypothesize that RPs play a major role in platelet-mediated IRI and that anagrelide alleviates IRI primarily by reducing the number of RPs in the peripheral circulation. To investigate this hypothesis, we have designed animal experiments and clinical trials. Ultimately, we have thoroughly examined potential limitations in confirming this hypothesis and have put forth strategies to effectively address and mitigate these challenges. [ABSTRACT FROM AUTHOR]

Highlights • Essential thrombocythemia (ET) has a risk of malignant transformation. • We determined transformation to acute myelogenous leukemia (AML). • Standardized incidence ratio of AML was high in ET patients on hydroxycarbamide. • No cases of AML occurred in ET patients treated with anagrelide. • Rates for non-AML cancers were similar in the two groups. Abstract EXELS, a post-marketing observational study, is the largest prospective study of high-risk essential thrombocythemia (ET) patients, with an observation time of 5 years. EXELS found higher event rates of acute leukemia transformation in patients treated with hydroxycarbamide (HC). In the current analysis, we report age-adjusted rates of malignant transformation from 3460 EXELS patients exposed to HC, anagrelide (ANA), or both. At registration, 481 patients had ANA treatment without HC exposure, 2305 had HC without ANA exposure, and 674 had been exposed to both. Standard incidence ratios (SIRs) were calculated using data from the Cancer Incidence in Five Continents database to account for differences in age-, gender-, and country-specific background rates. SIRs for acute myelogenous leukemia (AML) were high in ET patients. SIRs for AML were high in HC-treated patients, but AML was rare in ANA-treated patients; no cases of AML were found in patients only treated with ANA. No statistically significant difference was seen between SIRs for ANA and HC treatment for AML or skin cancer. SIRs for other cancers were similar in the HC and ANA groups and close to 1, indicating little difference in risk. Although statistically inconclusive, this study strengthens concerns regarding possible leukemogenic risk with HC treatment. (NCT00202644) [ABSTRACT FROM AUTHOR]

Cytoreductive therapy is used in high-risk essential thrombocythemia (ET) to reduce risk of thrombohemorrhagic complications. Anagrelide is an orally active, quinazolone-derived platelet-lowering agent approved for first-line treatment of high-risk ET in Japan. Long-term safety and efficacy data were collected from 53 Japanese high-risk ET patients (Study 308); 41 patients who completed Study 308 entered this phase 3b, open-label extension (Study 309; NCT01467661). Reductions in mean platelet counts occurred throughout the study, from 1021.6 × 109/L (at Study 308 baseline) to 675.4 × 109/L at final assessment. At month 48 (since Study 308 enrollment), mean platelet count was 444.5 × 109/L in the 10 patients who completed 4 years of therapy. Overall, platelet counts decreased from 1088.3 × 109/L at Study 308 baseline (n = 33) to 473.5 × 109/L at final assessment (n = 31). Long-term platelet count reductions were maintained without marked changes in mean anagrelide dose. Anagrelide was generally well tolerated, with anemia (54.7%) and headache (49.1%) as the most frequent adverse events. These findings indicate that anagrelide effectively reduces platelet counts in high-risk Japanese ET patients, with titration resulting in a well-tolerated, effective and sustainable dose. In conclusion, these results support anagrelide administration to high-risk Japanese ET patients using individualized dosing strategies defined in instructions previously approved in Europe and the USA. [ABSTRACT FROM AUTHOR]

Summary: Somatic mutations in the calreticulin (CALR) gene have been found in most patients with JAK2‐ and MPL‐unmutated Philadelphia chromosome‐negative myeloproliferative neoplasms (MPNs). It has recently been shown that mutant CALR constitutively activates the thrombopoietin receptor MPL and, thus, plays a causal role in the development of MPNs. However, the roles of mutant CALR in human haematopoietic cell differentiation remain predominantly elusive. To examine the impact of the 5‐base insertion mutant CALR gene (Ins5) on haematopoietic cell differentiation, we generated induced pluripotent stem cells from an essential thrombocythaemia (ET) patient harbouring a CALR‐Ins5 mutation and from a healthy individual (WT). Megakaryopoiesis was more prominent in Ins5‐haematopoietic progenitor cells (Ins5‐HPCs) than in WT‐HPCs, implying that the system recapitulates megakaryocytosis observed in the bone marrow of CALR‐mutant ET patients. Ins5‐HPCs exhibited elevated expression levels of GATA1 and GATA2, suggesting a premature commitment to megakaryocytic differentiation in progenitor cells. We also demonstrated that 3‐hydroxy anagrelide markedly perturbed megakaryopoiesis, but not erythropoiesis. Collectively, we established an in vitro model system that recapitulates megakaryopoiesis caused by mutant CALR. This system can be used to validate therapeutic compounds for MPN patients harbouring CALR mutations and in detailed studies on mutant CALR in human haematological cell differentiation. [ABSTRACT FROM AUTHOR]

Background: Anagrelide is an established treatment option for essential thrombocythemia (ET). Cardiovascular adverse events can occur with its use including heart failure and cardiomyopathy. Case Report: A 52-year-old African American male with ET presented with chest pain, shortness of breath, and dyspnea on exertion. His ET was managed with hydroxyurea 1500 mg by mouth twice a day and anagrelide 1 mg by mouth 3 times a day. The patient was receiving anagrelide for approximately 2 years prior to presentation. The patient’s platelet count was 2.07 × 105 cells/mm3. Transthoracic echocardiography revealed decreased left systolic dysfunction. Also, cardiac magnetic resonance imaging showed an increased left ventricle cavity size with severely depressed systolic dysfunction and an ejection fraction (EF) of 18%. Anagrelide therapy was discontinued and the patient was maintained on hydroxyurea for ET. Three months later, following treatment by a heart failure clinic, the patient’s EF was 55%. Five months after discontinuation, the patient improved from New York Heart Association (NYHA) class II to NYHA class I. Conclusion: A 52-year-old man with ET presented with an EF of 18% after 2 years of anagrelide therapy. His EF increased from 18% to 55% 3 months after discontinuation of anagrelide. [ABSTRACT FROM AUTHOR]

Hydroxycarbamide (HC) is the first-line treatment for certain myeloproliferative neoplasms, such as polycythemia vera and essential thrombocytosis (ET). In a subset of these patients long-term treatment with HC can result in the development of confluent actinic keratoses (AK) followed by invasive keratinocytic carcinomas (“squamous dysplasia”), preferentially on sun-exposed skin. Discontinuation or dose reduction of HC may result in partial improvement. A 59-year-old farmer after 14 years on HC (2 gr/d) and acetylsalicylic acid (100 mg/d) for ET, was referred for numerous, hyperkeratotic AK on face, scalp, and hands that could not be controlled with repeated (N=15) cryosurgery sessions in the previous 3 years. Acitretin (0.32 mg/kg daily) and topical treatments (cryosurgery with ingenol mebutate) were initiated with only marginal improvement after 3 months. Acitretin dose was doubled and HC was switched to anagrelide (0.5 mg twice daily). Within a month the AK load regressed significantly and, at 3 months follow-up, complete clinical remission was achieved and acitretin was discontinued. Twenty months later the patient is clear from AK. In conclusion, the impressive and sustainable AK remission under anagrelide draws attention to a possible role of the phosphodiesterase 3 pathway, the major pharmacological target of anagrelide, as a potential therapeutic target for keratinocytic cancers. [ABSTRACT FROM AUTHOR]

Abstract: Anagrelide is an established therapy for essential thrombocythemia. Common adverse effects have been linked to peak plasma concentrations of anagrelide and its 3OH metabolite. Our study was performed to investigate the pharmacokinetics (PK) of a novel anagrelide extended‐release (AER) formulation and its active metabolites. Thirty healthy volunteers were randomized to receive either 2 mg AER (under fasting and fed conditions) or 2 mg commercially available reference product (CARP) in an open‐label, 3‐way crossover trial with washout periods of 6 days. Plasma concentrations of anagrelide and its active metabolites were assessed by tandem mass spectrometry. The PK differed significantly between all treatment periods. Bioavailability of AER was 55% of the CARP under fasting conditions and 60% under fed conditions. Cmax, AUCt, and AUC∞ were significantly higher and Tmax and T1/2 were significantly shorter after the CARP compared with AER. Food had a significant impact on the PK of AER, increasing the Cmax and AUCt while reducing the T1/2, plateau, and mean residence time. Both formulations were well tolerated, with a trend toward more frequently occurring adverse events after the CARP. The PK of AER and the CARP differed significantly in all parameters. Food enhanced the bioavailability of AER. [ABSTRACT FROM AUTHOR]

We report a case of Prinzmetal angina as inaugural manifestation of coronary disease, in a young adult male patient, recently started on anagrelide for essential thrombocythemia. Moderate proximal left anterior descendent coronary artery stenosis was documented by angiography, and interventional or surgical revascularization has been discussed. Patient's option was for medical therapy alone. Anagrelide was temporarily withdrawn and rechallenged uneventfully after a couple of months and clinical evolution is good at four years follow-up. The mechanism by which anagrelide could induce coronary spasm and ischemia remains to be clarified. [ABSTRACT FROM AUTHOR]

Extreme thrombocytosis induces an acquired thrombotic-hemorrhagic diathesis, and left uncontrolled is a harbinger of potentially fatal vascular complications. Currently, cytoreduction with medical therapy remains the mainstay of hyperthrombocytosis management. However, it offers a less-than-ideal option in situations where a rapid reduction in platelets is urgently needed, as in the presence of vital end-organ ischemia or to ameliorate of life-threatening hemorrhage. The role of thrombocytapheresis, or plateletpheresis, in hyperthrombocytosis has become increasingly obsolete given the proactive titration of cytoreductive therapies and early identification and correction of reversible causes of reactive thrombocytosis. Despite its narrowed indications, plateletpheresis continues to offer a valuable temporizing measure in platelet count reduction before cytoreductive agents exert their maximal effect. In this context, it is important for the treating physician to be aware of the symptoms and risks associated with hyperthrombocytosis to inform best clinical practices. In this review, we discuss the role of plateletpheresis in the modern-day management of hyperthrombocytosis in patients with myeloproliferative neoplasms through a case based review of the literature. It becomes apparent throughout the discussion that the decision to perform plateletpheresis should be individualized based upon the clinical scenario, degree of thrombocytosis, available infrastructure and every patient’s risk profile. [ABSTRACT FROM AUTHOR]

Aim of this study is to explore the role of different treatments on the development of secondary malignancies ( SMs) in a large cohort of essential thrombocythemia ( ET) patients. We report the experience of a regional cooperative group in a real-life cohort of 1026 patients with ET. We divided our population into five different groups: group 0, no treatment; group 1, hydroxyurea ( HU); group 2, alkylating agents ( ALK); group 3, ALK + HU sequentially or in combination; and group 4, anagrelide ( ANA) and/or α-interferon ( IFN) only. Patients from groups 1, 2, and 3 could also have been treated either with ANA and/or IFN in their medical history, considering these drugs not to have an additional cytotoxic potential. In all, 63 of the 1026 patients (6%) developed 64 SM during the follow-up, after a median time of 50 months (range: 2-158) from diagnosis. In univariate analysis, a statistically significant difference was found only for gender ( P = 0.035) and age ( P = 0.0001). In multivariate analysis, a statistically significant difference was maintained for both gender and age (gender HR1.7 [ CI 95% 1.037-2.818] P = 0.035; age HR 4.190 [ CI 95% 2.308-7.607] P = 0.0001). The impact of different treatments on SMs development was not statistically significant. In our series of 1026 ET patients, diagnosed and followed during a 30-year period, the different therapies administered, comprising HU and ALK, do not appear to have impacted on the development of SM. A similar rate of SMs was observed also in untreated patients. The only two variables which showed a statistical significance were male gender and age >60 years. [ABSTRACT FROM AUTHOR]

BACKGROUND Essential thrombocytaemia is a myeloproliferative disease, characterized by an increased number of platelets in the peripheral blood, due to an increased production of such particles by the bone marrow. The primary event is the abnormal proliferation of megacariocytes. The objectives of treatment are the reduction of thrombohaemorragic events that occur in the course of the disease in high risk patients, because life expectancy is not affected. Nowadays hydroxyurea is the drug of choice to this purpose, but its use was related to a leukemogenic effect, although clinical data are still controversial. MECHANISMS OF ACTION Anagrelide is an oral agent that is able to significatively reduce the platelets count in these patients without effects on cell replication and nucleic acid synthesis. The mechanisms of action of this drug affect maturation, differentiation and growth of megacariocytes, by reducing intracellular cyclic AMP. Because the drug acts by inhibiting the phosphodiesterase enzyme, there are some important cardiovascular side effects, like vasodilatation, tachycardia, increase in cardiac output and hypotension. THERAPEUTIC EFFICACY AND STRATEGY Like hydroxyurea, anagrelide reduces the occurrence of thrombohaemorragic events in these patients, but venous thrombosis is more reduced than arterial, expecially when compared with hydroxyurea. To date, the role of anagrelide in the treatment of essential thrombocytaemia is the therapy of patients intolerant or refractory to the hydroxyurea: in perspective, its use could be proposed in younger patients (expecially women with child bearing potential) for long term treatment, or as second choice (after interferon) in pregnant women.

Objective To evaluate the reduction in thrombotic events ( TE) in patients with essential thrombocythaemia ( ET) treated with anagrelide versus hydroxyurea + aspirin ( HU + ASA). Methods A questionnaire was developed using 2008 WHO diagnostic criteria, and thrombotic risk factors were stratified according to Landolfi criteria. Through questionnaire completion, clinicians at Hungarian haematological centres entered data into the Hungarian MPN Registry on patients with myeloproliferative neoplasms. Based on ET registry data, TEs in anagrelide-treated patients ( n = 139) were compared with HU + ASA-treated patients ( n = 141). Results Patients were followed up for (median) 6 yr. TEs were reported in significantly fewer anagrelide-treated patients versus HU + ASA (15.1% versus 49.6%; P < 0.001). Numbers of major arterial and major venous events were similar between the groups, although there were over fivefold more minor arterial and minor venous events in the HU + ASA group ( P < 0.001). While median age at diagnosis was older and length of follow-up shorter in the HU + ASA group ( P < 0.05), this did not influence TE incidence; medication and TE before diagnosis only influenced TE incidence. Conclusions Anagrelide significantly decreased the number of patients experiencing minor arterial and minor venous TEs versus HU + ASA over 6 yr. Risk of TE after diagnosis was significantly increased if the patient had TE before diagnosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Anagrelide is an orally active, quinazolone-derived, platelet-lowering agent that acts by blocking megakaryocyte maturation and polyploidization as well as proplatelet formation, and is currently indicated for second-line treatment of high-risk patients with essential thrombocythemia (ET) in Europe. In recent years various clinical trials have confirmed the safety and efficacy of this drug in ET, with some also considering Janus kinase 2 ( JAK2) mutational status, but have not confirmed the impact that the other driver mutations, i.e., calreticulin ( CALR) and myeloproliferative leukemia virus ( MPL), may have on the response to this therapy. Objective: To assess the impact of JAK2, MPL, CALR gene mutational status on response to anagrelide therapy in patients with ET treated at the Oncohematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan between 2004 and 2015. Methods: Among 213 ET patients who were diagnosed between January 1983 to November 2014, 21 consecutive cases who were started on anagrelide as a second-line therapy and received at least 1-year of treatment were included. Inclusion criteria were the availability of demographic, clinical, histological, and hematologic data at diagnosis, and at least one granulocyte DNA sample to assess the mutational status of the JAK2, MPL, and CALR genes. Results: The JAK2V617F mutation was detected in seven patients (33.3 %), CALR mutations were identified in another seven cases, and the remaining seven patients were defined as 'triple-negative' (i.e., no JAK2, CALR, or MPL mutation). After a median anagrelide treatment duration of 4.6 years, 16 of 21 patients (76.2 %) achieved at least a partial platelet response: in particular, the hematological response rate was substantially comparable between JAK2-positive and 'triple-negative' patients, whereas the five patients who did not achieve any platelet response all had CALR mutations. Conclusion: Although it needs to be confirmed with a larger number of ET patients treated with anagrelide, we suggest that mutational status should be considered carefully when deciding on the most appropriate therapy for each patient, mainly because anagrelide alone was not able to achieve an appropriate hematological response in CALR-mutated ET cases. [ABSTRACT FROM AUTHOR]

Background: Anagrelide represents a treatment option for essential thrombocythemia, although its place in therapy remains controversial. Aim: To assess the impact of mutational status in response rates and development of adverse events during long-term use of anagrelide. Methods: We retrospectively evaluated 67 patients with essential thrombocythemia treated with anagrelide during 68 (4-176) months. Results: Mutational frequencies were 46.3%, 28.3%, and 1.5% for JAK2V617F, CALR and MPL mutations. Anagrelide yielded a high rate of hematologic responses, which were complete in 49.25% and partial in 46.25%, without differences among molecular subsets. The rate of thrombosis during treatment was one per 100 patient-years, without excess bleeding. Anemia was the major adverse event, 30.3% at 5-yr follow-up, being more frequent in CALR+ (P < 0.05). Myelofibrotic transformation developed in 14.9% (12.9%, 21%, and 12.5% in JAK2V617F+, CALR+, and triple-negative patients, respectively, P = NS) and those treated >60 months were at higher risk, OR (95% CI) 9.32 (1.1-78.5), P < 0.01, indicating the need for bone marrow monitoring during prolonged treatment. Conclusion: Although CALR+ patients were at higher risk of developing anemia, anagrelide proved effective among all molecular subsets, indicating that mutational status does not seem to represent a major determinant of choice of cytoreductive treatment among essential thrombocythemia therapies. [ABSTRACT FROM AUTHOR]

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. • Long-time anagrelide exposure results in progressive anemia in ET patients. • Anagrelide pro-anemic effect is driven by erythropoietin resistance. • CALR- mutated patients are particularly susceptible to anagrelide-induced anemia. [ABSTRACT FROM AUTHOR]

Controversies still exist regarding definition of the thrombotic risks in Ph- (BCR/ABL1-) myeloproliferative disorders with thrombocythemia (MPD-T). Platelet counts at diagnosis are currently not taken as a risk factor of thrombosis. In our cohort of 1179 patients with MPD-T, prospectively registered for anagrelide treatment, we found that the median platelet count prior to the thrombotic event was significantly higher than at time points without any ensuing thrombosis (453 vs. 400 9 109/L, P < 0.001), albeit higher platelet counts at diagnosis tended to be connected with fewer thrombotic events (in contrast to WBC counts at diagnosis). The JAK2V617F mutation predicted both arterial and venous events, while age >65 yr, hypertension, diabetes mellitus, smoking, elevated triglyceride and homocysteine levels predicted arterial events only. For venous events, the specific thrombophilic risk factors (factor V 'Leiden' and others), antiphospholipid antibodies, and elevated factor VIII levels played a major role. During anagrelide treatment (± aspirin), we documented a decrease in both venous (6.7-fold) and arterial events (1.8-fold), while bleeding (mostly minor events) increased twofold compared to history. Our results suggest that keeping platelet counts at low levels may be a meaningful therapeutic measure to prevent thrombosis, although their counts at diagnosis lack any prognostic value. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In this prospective observational single-center study, 55 patients with essential thrombocythemia who were candidates for second line treatment with anagrelide (ANA) received a preliminary cardiovascular (CV) clinical, instrumental and biochemical evaluation (CV history and symptoms, CV risk factors, blood pressure, heart rate, ECG and ECHO-cardio parameters, Troponin I, NT-proBNP). After this in-depth CV screening, 54 out of 55 patients were deemed to be fit for ANA treatment. Thirty-eight of the 55 patients received ANA treatment for a median of 36 months (range 3–48), and were monitored using the same CV evaluation. Fourteen of these 38 patients manifested CV adverse events (10 palpitation, 4 edema, 2 arterial hypertension, 2 acute myocardial infarction) that were not predicted by the in-depth CV evaluation, and that led to ANA withdrawal in only one case (non-cardiac refractory edema). In conclusion, the planned in-depth CV evaluation did not appear to be necessary in ET patients to evaluate their suitability for ANA treatment, and, moreover, was not able to predict the occurrence of CV adverse events during ANA treatment. Nevertheless, the CV adverse events (mostly palpitations and edema) were easily managed by the hematologists, and required the cardiologist involvement in very few selected cases. [ABSTRACT FROM AUTHOR]