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Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Jul 2015To evaluate the efficacy and safety of anagrelide in essential thrombocythemia (ET). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate the efficacy and safety of anagrelide in essential thrombocythemia (ET).
METHODS
Patients who diagnosed as ET according to the World Health Organization classification were enrolled. Each patient was assigned to take anagrelide hydrochloride capsule or hydroxyurea tablet by random 1∶1 ratio. Dose of anagrelide started at 2 mg/d, then increased gradually and the maximum dose was 10 mg/d until the platelet counts dropped to (100-400) × 10⁹/L, one month later gradually reduced to maintain dose. The dose of hydroxyurea was 1000 mg/d at beginning, then increased gradually, when platelet counts dropped to (100-400)×10⁹/L and kept for one month, reduced to maintain dose as 10 mg·kg⁻¹·d⁻¹. The observation period was 12 weeks.
RESULTS
A total of 222 patients were enrolled in seventeen centers (including 113 patients treated with anagrelide and 109 with hydroxyurea). Therapy efficacy can be evaluated in 198 patients (including 97 patients administered with anagrelide and 101 with hydroxyurea). At 12th weeks of therapy, the hematologic remission rate was 87.63% (85/97) in anagrelide group and 88.12% (89/107) in hydroxyurea group, the differences between the two groups were not significant (P=0.173). Treatment with anagrelide lowered the platelet counts by a median of 393 (362-1 339) × 10⁹/L from a median of 827 (562-1657) × 109/L at the beginning of the observation to 400(127-1130)×10⁹/L after 12 weeks (P<0.001), which were similar to the treatment result of hydroxyurea by a median drop of 398 (597-1846)× 10⁹/L (P=0.982). The median time to achieving response of anagrelide group was 7 (3-14) days, superior to that of hydroxyurea for 21 (14-28) significantly (P=0.003). Frequency of anagrelide related adverse events was 65.49 % (74/113), including cardiopalmus (36.28% ), headache (21.24% ), fatigue (14.16% ) and dizzy (11.50% ).
CONCLUSION
Anagrelide was effective in patients with ET which had similar hematologic remission rate to hydroxyurea and could take effect more quickly than hydroxyurea. Incidence of adverse events was undifferentiated between anagrelide and hydroxyurea, but anagrelide treatment had tolerable adverse effects and no hematologic toxicity.
Topics: Humans; Hydroxyurea; Platelet Aggregation Inhibitors; Platelet Count; Quinazolines; Thrombocythemia, Essential; Treatment Outcome
PubMed: 26304075
DOI: 10.3760/cma.j.issn.0253-2727.2015.07.00 -
Case Reports in Hematology 2015Hydroxycarbamide is used in the treatment of essential thrombocytosis and other myeloproliferative disorders. We report the case of a 63-year-old woman with essential...
Hydroxycarbamide is used in the treatment of essential thrombocytosis and other myeloproliferative disorders. We report the case of a 63-year-old woman with essential thrombocytosis who had melanonychia after the long-term use of the hydroxycarbamide with a dose of 1000 mg/day. Two years after the initiation of the hydroxycarbamide, our patient had pain on her toes and melanonychia on her nails. Hydroxycarbamide treatment was discontinued because of pain and she was given anagrelide treatment. The pathogenesis of melanonychia secondary to long-term hydroxycarbamide treatment is not yet well understood. Some investigators suggested that genetic factors, induction of melanocytes, and some changes in nail matrix could be the reason of hydroxycarbamide related melanonychia. Our patient has suffered color changes in her nails as well as pain that made us doubtful for a beginning of ulceration besides melanonychia. Maybe early clinical reaction of discontinuation of the drug has prevented more severe side effect like ulceration in our patient. Also side effect of hydroxycarbamide has developed more slowly in our patient compared to other patients in the mentioned study. To conclude, long-term hydroxycarbamide treatment can cause mucocutaneous side effects and more studies should be done in future in order to reveal the underlying mechanism.
PubMed: 26301108
DOI: 10.1155/2015/653178 -
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 -
Drug Design, Development and Therapy 2015A JAK2(V617F) mutation is found in approximately 55% of patients with essential thrombocythemia (ET), and represents a key World Health Organization diagnostic... (Observational Study)
Observational Study
A JAK2(V617F) mutation is found in approximately 55% of patients with essential thrombocythemia (ET), and represents a key World Health Organization diagnostic criterion. This hypothesis-generating study (NCT01352585) explored the impact of JAK2(V617F) mutation status on treatment response to anagrelide in patients with ET who were intolerant/refractory to their current cytoreductive therapy. The primary objective was to compare the proportion of JAK2-positive versus JAK2-negative patients who achieved at least a partial platelet response (≤600×10(9)/L) after anagrelide therapy. Of the 47 patients enrolled, 46 were included in the full analysis set (JAK2-positive, n=22; JAK2-negative, n=24). At 12 months, 35 patients (n=14 and n=21, respectively) had a suitable platelet sample; of these, 74.3% (n=26) achieved at least a partial response. The response rate was higher in JAK2-positive (85.7%, n=12) versus JAK2-negative patients (66.7%, n=14) (odds ratio [OR] 3.00; 95% confidence interval [CI] 0.44, 33.97). By using the last observation carried forward approach in the sensitivity analysis, which considered the imbalance in patients with suitable samples between groups, the overall response rate was 71.7% (n=33/46), with 77.3% (n=17/22) of JAK2-positive and 66.7% (n=16/24) of JAK2-negative patients achieving at least a partial response (OR 1.70; 95% CI 0.39, 8.02). There was no significant change in median allele burden over 12 months in the 12 patients who achieved a response. In conclusion, the overall platelet response rate was high in both JAK2-positive and JAK2-negative patients; however, a larger study would be required to confirm the differences observed according to JAK2(V617F) mutation status.
Topics: Adult; Aged; Aged, 80 and over; Alleles; Blood Platelets; Female; Humans; Janus Kinase 2; Male; Middle Aged; Mutation; Platelet Aggregation Inhibitors; Quinazolines; Thrombocythemia, Essential; Treatment Outcome
PubMed: 26028965
DOI: 10.2147/DDDT.S79576 -
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 -
Journal of Thrombosis and Haemostasis :... Jun 2015Anagrelide is a cytoreductive agent used to lower platelet counts in essential thrombocythemia. Although the drug has been known to selectively inhibit megakaryopoiesis...
BACKGROUND
Anagrelide is a cytoreductive agent used to lower platelet counts in essential thrombocythemia. Although the drug has been known to selectively inhibit megakaryopoiesis for many years, the molecular mechanism accounting for this activity is still unclear.
OBJECTIVES AND METHODS
To address this issue we have compared the global gene expression profiles of human hematopoietic cells treated ex-vivo with and without anagrelide while growing under megakaryocyte differentiation conditions, using high-density oligonucleotide microarrays. Gene expression data were validated by the quantitative polymerase chain reaction and mined to identify functional subsets and regulatory pathways.
RESULTS
We identified 328 annotated genes differentially regulated by anagrelide, including many genes associated with platelet functions and with the control of gene transcription. Prominent among the latter was TRIB3, whose expression increased in the presence of anagrelide. Pathway analysis revealed that anagrelide up-regulated genes that are under the control of the transcription factor ATF4, a known TRIB3 inducer. Notably, immunoblot analysis demonstrated that anagrelide induced the phosphorylation of eIF2α, which is an upstream regulator of ATF4, and increased ATF4 protein levels. Furthermore, salubrinal, an inhibitor of eIF2α dephosphorylation, increased the expression of ATF4-regulated genes and blocked megakaryocyte growth.
CONCLUSIONS
These findings link signaling through eIF2α/ATF4 to the anti-megakaryopoietic activity of anagrelide and identify new potential modulators of megakaryopoiesis.
Topics: Activating Transcription Factor 4; Cell Cycle Proteins; Cell Proliferation; Cells, Cultured; Computational Biology; Databases, Genetic; Eukaryotic Initiation Factor-2; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Hematologic Agents; Humans; Megakaryocytes; Oligonucleotide Array Sequence Analysis; Phosphorylation; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Quinazolines; Repressor Proteins; Signal Transduction; Thrombopoiesis; Time Factors
PubMed: 25851510
DOI: 10.1111/jth.12959 -
Journal of Thrombosis and Haemostasis :... Apr 2015Anagrelide represents a treatment option for essential thrombocythemia patients. It lowers platelet counts through inhibition of megakaryocyte maturation and...
BACKGROUND AND OBJECTIVES
Anagrelide represents a treatment option for essential thrombocythemia patients. It lowers platelet counts through inhibition of megakaryocyte maturation and polyploidization, although the basis for this effect remains unclear. Based on its rapid onset of action, we assessed whether, besides blocking megakaryopoiesis, anagrelide represses proplatelet formation (PPF) and aimed to clarify the underlying mechanisms.
METHODS AND RESULTS
Exposure of cord blood-derived megakaryocytes to anagrelide during late stages of culture led to a dose- and time-dependent inhibition of PPF and reduced proplatelet complexity, which were independent of the anagrelide-induced effect on megakaryocyte maturation. Whereas anagrelide was shown to phosphorylate cAMP-substrate VASP, two pharmacologic inhibitors of the cAMP pathway were completely unable to revert anagrelide-induced repression in megakaryopoiesis and PPF, suggesting these effects are unrelated to its ability to inhibit phosphodiesterase (PDE) 3. The reduction in thrombopoiesis was not the result of down-regulation of transcription factors which coordinate PPF, while the myosin pathway was identified as a candidate target, as anagrelide was shown to phosphorylate the myosin light chain and the PPF phenotype was partially rescued after inhibition of myosin activity with blebbistatin.
CONCLUSIONS
The platelet-lowering effect of anagrelide results from impaired megakaryocyte maturation and reduced PPF, both of which are deregulated in essential thrombocythemia. These effects seem unrelated to PDE3 inhibition, which is responsible for anagrelide's cardiovascular side-effects and antiplatelet activity. Further work in this field may lead to the potential development of drugs to treat thrombocytosis in myeloproliferative disorders with an improved pharmacologic profile.
Topics: Blood Platelets; Case-Control Studies; Cell Adhesion Molecules; Cells, Cultured; Cyclic AMP; Dose-Response Relationship, Drug; Fetal Blood; Hematopoietic Stem Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Megakaryocytes; Microfilament Proteins; Myosins; Phosphodiesterase 3 Inhibitors; Phosphoproteins; Phosphorylation; Platelet Aggregation Inhibitors; Quinazolines; Signal Transduction; Thrombocythemia, Essential; Thrombopoiesis; Time Factors; Transcription Factors
PubMed: 25604267
DOI: 10.1111/jth.12850 -
F1000Research 2014Essential thrombocythemia is a clonal myeloproliferative neoplasm characterized by an elevated platelet count, the potential for both microvascular and macrovascular...
Essential thrombocythemia is a clonal myeloproliferative neoplasm characterized by an elevated platelet count, the potential for both microvascular and macrovascular sequelae, and a risk for transformation to myelofibrosis or acute myeloid leukemia. A systematic and detailed initial analysis is essential for accurate diagnosis of essential thrombocythemia, as many etiologies are reactive and benign. Once a diagnosis has been made, risk stratification and symptom assessment are vital to guide the subsequent therapy. Treatment may be required in high-risk disease, such as in cases of advanced age or prior thrombotic events. Systemic therapy is aimed at reducing the thrombotic risk and includes daily low dose aspirin and in some patients, cytoreductive therapy. Currently, the first line cytoreductive therapy includes hydroxyurea or pegylated interferon, with a phase III clinical trial underway comparing these two important agents. Anagrelide and clinical trials are reserved for refractory or intolerant patients. Looking to the future, new therapies including Janus kinase 2 (JAK2) and telomerase inhibitors are promising and may become valuable to the treatment armamentarium for those afflicted with essential thrombocythemia.
PubMed: 25324966
DOI: 10.12688/f1000research.5361.1 -
Acta Haematologica 2015
Essential differences in clinical and bone marrow features in BCR/ABL-positive thrombocythemia compared to thrombocythemia in the BCR/ABL-negative myeloproliferative neoplasms essential thrombocythemia and polycythemia vera.
Topics: Aged; Alleles; Benzamides; Biopsy; Bone Marrow; Diagnosis, Differential; Drug Therapy, Combination; Female; Fusion Proteins, bcr-abl; Humans; Hydroxyurea; Imatinib Mesylate; Janus Kinase 2; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Piperazines; Platelet Count; Polycythemia Vera; Pyrimidines; Quinazolines; Thrombocythemia, Essential; Treatment Outcome
PubMed: 25116159
DOI: 10.1159/000358915 -
Actas Dermo-sifiliograficas Nov 2014
Topics: Aged; Dermatomyositis; Diagnosis, Differential; Drug Eruptions; Drug Substitution; Erythema; Female; Humans; Hydroxyurea; Leg Ulcer; Lichenoid Eruptions; Precancerous Conditions; Primary Myelofibrosis; Quinazolines
PubMed: 24666578
DOI: 10.1016/j.ad.2014.02.003