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Internal Medicine (Tokyo, Japan) Nov 2022Anagrelide is used worldwide to treat essential thrombocythemia (ET) by reducing platelet counts. Cardiomyopathy and heart failure (HF) are rare but serious... (Review)
Review
Anagrelide is used worldwide to treat essential thrombocythemia (ET) by reducing platelet counts. Cardiomyopathy and heart failure (HF) are rare but serious complications associated with anagrelide use, although no cases were reported during Japanese Phase I to III studies. A 46-year-old, otherwise healthy, Japanese ET patient developed HF with reduced ejection fraction after 18 months of treatment with 1.0-3.5 mg of anagrelide daily. HF was stabilized with anagrelide withdrawal and guideline-directed HF therapy. The cardiac function returned to normal after six months. This case suggests that anagrelide can cause cardiomyopathy and HF in ET patients, regardless of nationality, comorbid cardiovascular conditions, or therapy duration.
Topics: Humans; Middle Aged; Thrombocythemia, Essential; Platelet Aggregation Inhibitors; Cardiomyopathies; Heart Failure
PubMed: 35342135
DOI: 10.2169/internalmedicine.9090-21 -
South Dakota Medicine : the Journal of... Nov 2021Anagrelide is a drug used for treatment of essential thrombocytosis especially when conventional therapy is insufficient. Adverse effects associated with anagrelide are...
BACKGROUND
Anagrelide is a drug used for treatment of essential thrombocytosis especially when conventional therapy is insufficient. Adverse effects associated with anagrelide are palpitation, liver toxicity, renal failure and in few cases pericardial effusion. We here report a rare case of anagrelide induced pericardial effusion.
CASE PRESENTATION
A 76-year-old male with past medical history of hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and myeloproliferative disorder presented to the emergency department with dyspnea on rest and exertion. He was initially treated with hydroxyurea for thrombocytosis but was later switched to anagrelide. On examination patient had muffled heart sounds. Lab investigations identified hyperkalemia and transaminitis. Transthoracic echocardiogram identified a moderate sized pericardial effusion. The pericardial effusion and transaminitis were attributed to anagrelide toxicity as other causes were ruled out. Pericardiocentesis was performed and anagrelide was discontinued. Patient was discharged in a well-compensated state with outpatient follow-up in two to three weeks.
CONCLUSION
Anagrelide is considered to be very effective treatment for essential thrombocytosis. It is, however, associated with serious adverse effects such as pericardial effusion, liver toxicity and palpitations. The mechanisms of these adverse drug reactions are still not completely understood. We suggest that patient taking anagrelide presenting with shortness of breath should have a transthoracic echocardiogram performed to rule out pericardial effusion. Liver enzymes should also be monitored closely and anagrelide discontinued immediately if the above-mentioned adverse events are noted.
Topics: Aged; Humans; Male; Myeloproliferative Disorders; Platelet Aggregation Inhibitors; Thrombocytosis; Treatment Outcome
PubMed: 35008135
DOI: No ID Found -
BioDrugs : Clinical Immunotherapeutics,... Jun 2016Anagrelide is an orally active, quinazolone-derived, platelet-lowering agent that acts by blocking megakaryocyte maturation and polyploidization as well as proplatelet...
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.
Topics: Adult; Calreticulin; Female; Humans; Janus Kinase 2; Male; Middle Aged; Mutation; Platelet Aggregation Inhibitors; Quinazolines; Receptors, Thrombopoietin; Retrospective Studies; Thrombocythemia, Essential; Treatment Outcome
PubMed: 27041108
DOI: 10.1007/s40259-016-0170-9 -
American Society of Clinical Oncology... 2015The groundbreaking discovery of the Janus-associated kinase 2 (JAK2) V617F mutation 10 years ago resulted in an unprecedented intensive basic and clinical research in... (Review)
Review
The groundbreaking discovery of the Janus-associated kinase 2 (JAK2) V617F mutation 10 years ago resulted in an unprecedented intensive basic and clinical research in Philadelphia-negative myeloproliferative neoplasms (MPNs). During these years, many new potential targets for therapy were identified that opened the era of targeted therapy for these diseases. However, only one new drug (ruxolitinib) has been approved during the past 40 years, and, although promising new therapies are evaluated, the armamentarium to treat MPN still relies on conventional drugs, like cytotoxic agents and anagrelide. The exact role of interferon (IFN) alfa still needs to be clarified in randomized studies, although it has been shown to be effective in MPNs for more than 25 years. The current therapeutic strategy for MPNs is based on the risk of vascular complication, which is the main cause of mortality and mortality in the medium term. However, the long-term outcome may be different, with an increasing risk of transformation to myelodysplastic syndrome or acute leukemia during follow-up times. Medicines able to change this natural history have not been clearly identified yet, and allogeneic stem cell transplantation currently remains the unique curative approach, which is only justified for patients with high-risk myelofibrosis or for patients with MPNs that have transformed to myelodysplasia or acute leukemia.
Topics: Anemia; Antineoplastic Agents; Female; Forecasting; Hematopoiesis, Extramedullary; Humans; Janus Kinases; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Myeloproliferative Disorders; Phlebotomy; Polycythemia Vera; Pregnancy; Pregnancy Complications, Hematologic; Primary Myelofibrosis; Risk Assessment; Splenomegaly; Stem Cell Transplantation; Thrombocythemia, Essential
PubMed: 25993201
DOI: 10.14694/EdBook_AM.2015.35.e389 -
Current Opinion in Hematology Mar 2016Management of polycythemia vera and essential thrombocythemia requires understanding of the key concepts regarding diagnosis, risk stratification, and management. (Review)
Review
PURPOSE OF REVIEW
Management of polycythemia vera and essential thrombocythemia requires understanding of the key concepts regarding diagnosis, risk stratification, and management.
RECENT FINDINGS
Essential thrombocythemia and polycythemia vera are among the Philadelphia chromosome negative myeloproliferative neoplasms. They are characterized by overproduction of blood cells and their complications include thrombosis, hemorrhage, and progression to myelofibrosis or acute myeloid leukemia (AML). Management of essential thrombocythemia/polycythemia vera requires recognition of the risk factors for thrombosis and hemorrhage. Risk stratification allows the clinician to make a treatment plan that may include antiplatelet therapy with aspirin alone or in combination with therapeutic phlebotomy in the case of polycythemia vera, or cytoreductive therapy for high-risk patients with either essential thrombocythemia or polycythemia vera. Hydroxyurea remains first-line therapy for high-risk patients with essential thrombocythemia/polycythemia vera, whereas second-line options include anagrelide, pegylated-IFNα-2a, and the JAK1/2 inhibitor ruxolitinib. The current evaluation of pegylated-IFNα-2a in global phase II and III studies will provide clarity to the potential long-term benefit and risks associated with this biologic in patients with essential thrombocythemia/polycythemia vera. Novel therapeutics aimed at prevention of disease progression to myelofibrosis/AML are the focus of current clinical trials.
SUMMARY
Risk stratification of patients with essential thrombocythemia/polycythemia vera by age and/or history of thrombosis provides the basis of risk adapted therapeutic intervention. Aggressive control of modifiable cardiovascular risk factors, the use of antiplatelet agents, control of the hematocrit less than 45% in polycythemia vera, and cytoreductive therapy in high-risk essential thrombocythemia/polycythemia vera patients is the focus of management. The exact role of IFN-α remains undefined and under active investigation, and the recent approval of ruxolitinib provides patients with polycythemia vera a second-line option.
Topics: Combined Modality Therapy; Disease Management; Disease Progression; Humans; Polycythemia Vera; Risk; Thrombocythemia, Essential; Treatment Outcome
PubMed: 26717193
DOI: 10.1097/MOH.0000000000000216 -
Expert Review of Hematology Sep 2021Chronic myeloproliferative neoplasm (MPNs) are clonal malignant bone marrow (BM) diseases, arising from a hematopoietic stem cell. All therapies for these neoplasms... (Review)
Review
Chronic myeloproliferative neoplasm (MPNs) are clonal malignant bone marrow (BM) diseases, arising from a hematopoietic stem cell. All therapies for these neoplasms have peculiar effects on the bone marrow, but little evidence has been described in the literature. This review examines BM morphological changes following the main treatments in Philadelphia-negative MPNs. Hydroxyurea can reduce the cellularity of the erythroid and megakaryocyte lineages but has minimal impact on fibrotic evolution. There is general agreement on its dysplastic effects, with a high incidence of acute myeloid leukemia and myelodysplastic syndrome. Interferon treatment can reduce or normalize BM cellularity, improve erythropoiesis, and reduce the number and atypicality of megakaryocytes. Most data describe reduction or complete resolution of marrow fibrosis; dysplastic effects are not reported. Anagrelide may induce an increase in the number of BM megakaryocytes, especially immature megakaryocytes or precursors, and a worsening of marrow fibrosis or increased transformation of essential thrombocythemia into myelofibrosis. Ruxolitinib can improve or stabilize BM fibrosis and reduces the frequency and dense clustering of megakaryocytes. Since previous therapy can modify BM features, it is essential to obtain information on previous or current therapies and to collect complete clinical information.
Topics: Bone Marrow; Humans; Myeloproliferative Disorders; Neoplasms; Primary Myelofibrosis; Thrombocythemia, Essential
PubMed: 34384330
DOI: 10.1080/17474086.2021.1967138 -
Journal of Hematology Jun 2021Essential thrombocythemia (ET) is one of the "classic" Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms characterized by sustained thrombocytosis,...
BACKGROUND
Essential thrombocythemia (ET) is one of the "classic" Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms characterized by sustained thrombocytosis, increased megakaryopoiesis and high risk of vascular complications. ET is very rare in childhood. The annual incidence is approximately 1 per 10,000,000 in children less than 14 years, and about 60 times lower than adults. The genetic landscape and clonal features in childhood ET has not been well defined. There is no evidence-based guidance on the diagnosis of childhood ET.
METHODS
Medical records of 28 pediatric patients (age ≤ 14 years at diagnosis) with ET were reviewed and evaluated to characterize the different mutation profiles and to evaluate the treatment modalities used and the potential long-term outcome.
RESULTS
More than half of the patients were found to have positive history of parental consanguinity (57.1%) whereas positive family history was documented for more than a quarter of our patients (28.6%). Janus kinase 2 gene () V617F mutation was positive in two of 26 patients (7.7%). Myeloproliferative leukemia virus oncogene () exon 10 and calreticulin () mutations were tested in eight patients, which were negative for all of them. Treatment included low-dose aspirin (LDA) in seven patients (50%), combination of LDA with hydroxyurea in three patients (21.4%), hydroxyurea in two patients (14.3%), combination of platelets apheresis with LDA and anagrelide in one patient each (7.1%). During the treatment, two patients experienced stroke (7.1%), one patient developed Budd-Chiari syndrome (3.6%) and one patient developed azoospermia (3.6%).
CONCLUSIONS
The incidence of ET in children is extremely low in Saudi Arabia. Most of the children with ET were asymptomatic, and thrombocytosis was often discovered incidentally. V617F mutation has no known impact on the prognosis or on the outcome of the disease in the pediatric age group that is in contrast to the adult ET. Children less than 1 year are at high risk for complications particularly during acute precipitating infectious episode. The potential complications and clinical course of pediatric ET are unpredictable.
PubMed: 34267847
DOI: 10.14740/jh822 -
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 -
Therapeutic Advances in Hematology Jun 2015The new World Health Organization (WHO) diagnostic criteria for essential thrombocythemia (ET) issued in 2008 made an important distinction between true ET and early... (Review)
Review
The new World Health Organization (WHO) diagnostic criteria for essential thrombocythemia (ET) issued in 2008 made an important distinction between true ET and early myelofibrosis (MF), which has helped to identify a more homogenous population for the diagnosis with longer survival and much less transformation to overt MF. The recent finding of a new mutation (CALR), which is mutually exclusive with JAK2 and MPL mutations, adds to the characterization of ET patients, since there are important phenotypic differences between the mutation types. CALR patients are younger, have lower white blood cell counts (WBC) and a lower thrombosis incidence. A growing field of interest is the state of hypercoagulation due to dysfunction of hemostatic systems, cell-cell interaction and hereditary prothrombotic traits. Activation of platelets, WBC and endothelial cells has been found, making the whole intravascular milieu prothrombotic. Several risk score models, based on retrospective studies, have been developed lately, distinguishing patient groups with graded risk for complications and death. Even if these may be helpful in evaluating patients, they have not been validated in prospective studies and there are not enough data to support their use as a basis for treatment algorithms. The traditional risk factors age, previous thrombosis and platelets >1500 × 10(9)/l are still recommended for the distinction between high risk and low risk ET and the decision to give cytoreductive therapy. However, cardiovascular (CV) risk factors add to thrombosis risk and should be considered both for specific treatment in any risk group and for upgrading low risk patients with high CV risk to an intermediary group where active therapy with aspirin and cytoreduction may be considered. First-line cytoreductive therapy differs with age; in younger patients interferon (IFN) or anagrelide are preferable, in older patients hydroxycarbamide (HC). Second-line therapy for younger patients is HC, for older patients IFN or anagrelide (ANA). JAK2 inhibitors may be suitable in rare cases with symptoms not responding to other therapy.
PubMed: 26137205
DOI: 10.1177/2040620715580068 -
Journal of Cancer Research and Clinical... Nov 2016To review interactions between oral antineoplastic agents (OAAs) for the treatment of solid and hematological tumors and common food and medicinal plants. (Review)
Review
OBJECTIVE
To review interactions between oral antineoplastic agents (OAAs) for the treatment of solid and hematological tumors and common food and medicinal plants.
MATERIALS AND METHODS
All potential interactions between OAAs, medicinal plants and food were reviewed. OAAs were considered to be drugs for oral administration that have direct antitumor activity and were approved by the European Medicines Agency in April 2015. We performed the literature search in Pubmed(®) considering only medicinal plants and food. In addition, available data were analyzed from each OAA in secondary data sources taken from Thomson Micromedex(®) and Lexi-comp(®), as well as in the summary of product characteristics.
RESULTS
Fifty-eight OAAs were analyzed. We found interactions in 60.3 % of OAAs. Those with most interactions described were: imatinib and procarbazine (4 interactions) and erlotinib, vemurafenib, pomalidomide, medroxyprogesterone and methotrexate (3 interactions).
MEDICINAL PLANTS
We found 39 interactions (74.4 % important). St. John's wort was the medicinal plant with most interactions (92.6 % were considered important). The rest were: important (ginseng-imatinib, methotrexate-cola and tobacco-erlotinib and tobacco-pomalidomide) and moderate (caffeine-vemurafenib/medroxyprogesterone, medroxyprogesterone-ruxolitinib/St. John's wort, garlic-anagrelide and ginseng-procarbazine).
FOODS
Twenty-six interactions (61.5 % important). Grapefruit had most interactions (82.4 % were considered important). The rest were: important (alcohol-procarbazine) and moderate (dairy-estramustine, methotrexate-ethanol, procarbazine-tyramine, vitamin A-tretinoin/bexarotene and grapefruit-bexarotene/etoposide/sunitinib).
CONCLUSION
A review of interactions of medicinal plants and food should be taken into account in the management of OAAs, since more than half have interactions with MPs and food, of which 70.3 % are considered important. The most relevant are HSJ, grapefruit, ginseng and tobacco. This review is intended to serve as a support to all healthcare professionals at the time of prescribing or dispensing OAAs.
Topics: Administration, Oral; Antineoplastic Agents; Food-Drug Interactions; Humans; Plants, Edible; Plants, Medicinal
PubMed: 27316629
DOI: 10.1007/s00432-016-2190-8