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Cardiovascular Toxicology Mar 2021Essential thrombocythaemia (ET) is a rare myeloproliferative neoplasm. This multicentre, Phase 3b, randomised, open-label, non-inferiority study investigated the cardiac... (Comparative Study)
Comparative Study
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.
Topics: Adolescent; Adult; Aged; Biopsy; Blood Platelets; Bone Marrow Examination; Echocardiography; Europe; Female; Humans; Hydroxyurea; Male; Middle Aged; Platelet Count; Quinazolines; Stroke Volume; Thrombocythemia, Essential; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left; Young Adult
PubMed: 33123978
DOI: 10.1007/s12012-020-09615-0 -
Respiratory Medicine Case Reports 2020A-71-year-old woman was diagnosed as chronic thromboembolic pulmonary hypertension (CTEPH) accompanied by essential thrombocythemia (ET) with JAK2 V617F mutation. Blood...
Successful treatment for a patient with chronic thromboembolic pulmonary hypertension comorbid with essential thrombocythemia with the JAK2 V617F mutation by balloon pulmonary angioplasty.
A-71-year-old woman was diagnosed as chronic thromboembolic pulmonary hypertension (CTEPH) accompanied by essential thrombocythemia (ET) with JAK2 V617F mutation. Blood test showed remarkable increase of platelet counts (132.9 × 10^4/μL) and elevated plasma BNP level (125.1pg/mL). Right heart catheterization (RHC) revealed remarkably high mean pulmonary arterial pressure (mPAP) of 43 mmHg. We gave her riociguat of 7.5mg, oral anticoagulants, oxygen inhalation for CTEPH, and anagrelide for ET. We performed 4 sessions of balloon pulmonary angioplasty (BPA) in 9 months RHC revealed successful hemodynamic improvement (mPAP = 21 mmHg) after final BPA procedure without riociguat. At six month later after final BPA procedure, RHC showed steadily improvement of mPAP (21 mmHg) without riociguat and oxygen inhalation. She lives well without oxygen inhalation and PH targeted therapy. This is the first report of successful treatment for a patient with CTEPH comorbid with ET with JAK2 V617F mutation by BPA.
PubMed: 33024690
DOI: 10.1016/j.rmcr.2020.101235 -
European Journal of Haematology Jan 2021Cell counts have a significant impact on the complex mechanism of thrombosis in patients with essential thrombocythemia (ET). We recently demonstrated a considerable...
OBJECTIVES
Cell counts have a significant impact on the complex mechanism of thrombosis in patients with essential thrombocythemia (ET). We recently demonstrated a considerable impact of white blood cell (WBC) counts on thrombotic risk in patients with optimized platelet counts by analysing a large anagrelide registry. In contrast, the current analysis of the registry aimed to estimate the influence of platelet counts on thrombotic risk in patients with optimized WBC counts.
METHODS
Cox regression analysis and Kaplan-Meier plot were applied on all patients in the registry with optimized WBC counts.
RESULTS
By using the calculated cut-off of 593 G/L for platelets, Cox regression analysis revealed a clear influence of elevated platelet counts on the occurrence of a major thrombotic event (P < .001). A Kaplan-Meier plot revealed a markedly shorter time to a major thrombotic event for patients with platelet counts above the cut-off (P < .001).
CONCLUSIONS
The data show clear impact of platelet lowering on the thrombotic risk in ET patients with normal WBC counts. Therefore, selective platelet lowering with anagrelide appears sufficient for thrombotic risk reduction in WHO-diagnosed ET patients lacking leukocytosis.
Topics: Aged; Biomarkers; Blood Platelets; Disease Susceptibility; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leukocyte Count; Male; Middle Aged; Platelet Count; Prognosis; Registries; Thrombocythemia, Essential; Thrombosis
PubMed: 32909297
DOI: 10.1111/ejh.13516 -
Medicine Jul 2020Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension. It is often underdiagnosed or misdiagnosed as idiopathic pulmonary arterial...
INTRODUCTION
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension. It is often underdiagnosed or misdiagnosed as idiopathic pulmonary arterial hypertension (PAH). Inappropriate treatment may cause worsening of symptoms which may lead to fatal outcomes. Anesthetic considerations and management for pulmonary hypertension are well described, but few anesthesiologists are aware of the entity of PVOD and its management.
PATIENT CONCERNS
We report a case of PVOD in a 73-year-old female who was on concurrent aspirin and anagrelide, requiring emergent open femoral hernia repair.
DIAGNOSIS
PVOD and incarcerated femoral hernia INTERVENTION:: Combined spinal-epidural (CSE) was performed to enable the surgery.
OUTCOME
Surgery was completed successfully under central neuraxial anesthesia and the patient remained stable and comfortable throughout, avoiding the need for general anesthesia. Due to the concurrent aspirin and anagrelide therapy, significant bleeding from the CSE puncture site was observed immediately post-operatively. This was resolved with external manual compression and withholding the aspirin and anagrelide. Patient remained well without neurological deficit and was discharged postoperative day seven.
LESSONS
It is important to differentiate PVOD from PAH due to the controversial use of pulmonary vasodilators in PVOD. Pulmonary vasodilator is commonly used to treat acute pulmonary hypertension in PAH but its usage may lead to pulmonary edema in patients with PVOD. Hence, with no ideal treatment available, the avoidance of general anesthesia is crucial to prevent acute pulmonary hypertensive crisis in patient with PVOD. However, this needs to be weighed against the elevated risk of central neuraxial bleeding when performing a CSE in a patient on concurrent aspirin and anagrelide therapy. Calculated decision-making considering the risks and benefits of all alternatives should be carried out in such a scenario, and measures should be taken in anticipation of the potential consequences of the eventual decision.
CONCLUSION
It is important to differentiate PVOD from PAH. PVOD has unique anesthetic considerations due to the controversial use of pulmonary vasodilators. This case also emphasizes the importance of active anticipation of potential issues and adequate follow up.
Topics: Aged; Anesthesia, Epidural; Anesthesia, Spinal; Female; Hernia, Femoral; Herniorrhaphy; Humans; Intraoperative Complications; Pulmonary Veno-Occlusive Disease
PubMed: 32791767
DOI: 10.1097/MD.0000000000021517 -
British Journal of Haematology Mar 2021The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267... (Clinical Trial)
Clinical Trial Comparative Study
Cytoreductive treatment in patients with CALR-mutated essential thrombocythaemia: a study comparing indications and efficacy among genotypes from the Spanish Registry of Essential Thrombocythaemia.
The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR-mutated. In low risk patients, time from diagnosis to cytoreduction was shorter in CALR-positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR-mutated ET than in the remaining patients (P = 0·003). In CALR-positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR-mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR-mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Substitution; Calreticulin; Child; Female; Follow-Up Studies; Genotype; Humans; Hydroxyurea; Janus Kinase 2; Male; Middle Aged; Mutation, Missense; Quinazolines; Registries; Spain; Thrombocythemia, Essential
PubMed: 32745264
DOI: 10.1111/bjh.16988 -
Journal of Thrombosis and Thrombolysis Jan 2021Arterial thrombosis is a common complication in patients with Ph myeloproliferative neoplasms (MPN). We searched for the risk factors of stroke in MPN patients from...
Arterial thrombosis is a common complication in patients with Ph myeloproliferative neoplasms (MPN). We searched for the risk factors of stroke in MPN patients from anagrelide registry. We analyzed the potential risk factors triggering a stroke/TIA event in 249 MPN patients with previous stroke (n = 168) or Transient Ischemic Attack (TIA) (n = 140), and in 1,193 MPN control subjects (without clinical history of thrombosis). These patients were registered in a prospective manner, providing a follow-up period after Anagrelide treatment. The median age of the patients in the experimental group was of 56 years of age (ranging from 34-76) and of 53 years of age (ranging from 26-74) in the control group (p < 0.001). Using a multivariate model, we determined the following as risk factors: JAK2V617F mutation (OR 2.106, 1.458-3.043, p = 0.006), age (OR 1.017/year, 1.005-1,029, p = 0.006), male gender (OR 1.419, 1.057-1.903, p = 0.020), MPN diagnosis (OR for PMF 0.649, 0.446-0.944, p = 0.024), BMI (OR 0.687 for BMI > 25, 0.473-0.999, p = 0.05) and high TAG levels (OR 1.734, 1.162-2.586, p = 0.008), all of which were statistically significant for CMP development. Concerning the risk factors for thrombophilia, only the antiphospholipid syndrome (OR 1.994, 1.017-3.91, p = 0.048) was noteworthy in a stroke-relevant context. There was no significant difference between the blood count of the patients prior to a stroke event and the control group, both of which were under a cytoreductive treatment. We found that age, male gender, JAK2V617F mutation, previous venous thrombosis, and hypertriglyceridemia represent independent risk factors for the occurrence of a stroke in Ph MPN patients.
Topics: Adult; Aged; Female; Fibrinolytic Agents; Humans; Janus Kinase 2; Male; Middle Aged; Myeloproliferative Disorders; Quinazolines; Risk Factors; Stroke; Thrombosis
PubMed: 32578055
DOI: 10.1007/s11239-020-02175-8 -
Hematology (Amsterdam, Netherlands) Dec 2020Real-world data of responses, quality-of-life (QOL) changes and adverse events in patients with myeloproliferative neoplasms (MPN) on conventional therapy...
Myeloproliferative neoplasms treated with hydroxyurea, pegylated interferon alpha-2A or ruxolitinib: clinicohematologic responses, quality-of-life changes and safety in the real-world setting.
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. 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. Seventy men and fifty-five women with polycythemia vera (PV) ( = 23), essential thrombocythemia (ET) ( = 56) and myelofibrosis (MF) ( = 46) were studied for a median of 36 (range: 19-42) months. In PV, responses were comparable for different modalities. mutations were associated with inferior responses. In ET, PEG-IFNα-2A resulted in superior clinicohematologic complete responses (CHCR) (= 0.045). In MF, superior overall response rates (ORR) were associated with ruxolintib (= 0.018) and V617F mutation (= 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 ( < 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. 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.
Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Female; Humans; Hydroxyurea; Interferon-alpha; Male; Middle Aged; Myeloproliferative Disorders; Nitriles; Polyethylene Glycols; Prospective Studies; Pyrazoles; Pyrimidines; Quality of Life; Recombinant Proteins; Young Adult
PubMed: 32567517
DOI: 10.1080/16078454.2020.1780755 -
European Journal of Haematology Oct 2020We report an extension study of patients with essential thrombocythaemia (ET) in the Hungarian Myeloproliferative Neoplasm (HUMYPRON) Registry, which demonstrated that...
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.
Topics: Aspirin; Drug Therapy, Combination; Health Care Surveys; Humans; Hungary; Hydroxyurea; Quinazolines; Registries; Thrombocythemia, Essential; Thrombosis; Treatment Outcome
PubMed: 32557810
DOI: 10.1111/ejh.13459 -
European Journal of Haematology Sep 2020Anagrelide is a drug effective in reducing platelet counts in essential thrombocythemia (ET) and Ph1-negative myeloproliferative neoplasms. The aim of this study was to...
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.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anemia; Disease Management; Disease Susceptibility; Drug Substitution; Female; Follow-Up Studies; Health Care Surveys; Humans; Italy; Male; Middle Aged; Pregnancy; Pregnancy Complications, Hematologic; Prognosis; Quinazolines; Retreatment; Retrospective Studies; Thrombocythemia, Essential; Thrombosis; Treatment Outcome; Young Adult
PubMed: 32441419
DOI: 10.1111/ejh.13454