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HemaSphere Aug 2019We retrospectively evaluated 48 essential thrombocythemia (ET) patients who were treated in our institute (male/female, 14/34, median age, 61.5 years). In 14 patients...
We retrospectively evaluated 48 essential thrombocythemia (ET) patients who were treated in our institute (male/female, 14/34, median age, 61.5 years). In 14 patients treated with anagrelide (ANA), the degree of platelet count reduction (median, -56.6%) was strongly correlated with increase of mean platelet volume (MPV) (median, +11.7%) (R = 0.777). This correlation was not observed in ET patients treated with hydroxycarbamide alone (R = 0.245). The change in size of platelets strongly suggested that ANA affected the final process of platelet production. Thus, we hypothesized that ANA modifies the process by which platelets are released from proplatelets. To verify the association in an in vitro setting, we compared MEG-01 cells treated with PMA ± ANA. The number of platelet-like particles (PLPs) was decreased ( < 0.05) and the size of PLPs estimated by using flow cytometry was significantly increased when MEG-01 cells were treated with PMA + ANA ( < 0.05 vs PMA alone), recapitulating the clinical findings. The cytoplasmic protrusions extending from MEG-01 cells were shorter and thicker and the number of proplatelets was decreased when MEG-01 cells were treated with PMA + ANA ( < 0.01 vs PMA alone). Western blotting analysis showed that ANA treatment resulted in increased phosphorylation of MLC2 and reduced phosphorylation of focal adhesion kinase (FAK). The morphological change of proplatelets were reversed by blebbistatin, a specific inhibitor of myosin II. These findings indicated that ANA modulates the FAK-RhoA-ROCK-MLC2-myosine IIA pathway and suppresses proplatelet maturation, leading to a decrease in platelet count and increase in MPV.
PubMed: 31723843
DOI: 10.1097/HS9.0000000000000268 -
American Journal of Cancer Research 2019We performed a drug repurposing screening of a US Food and Drug Administration (FDA)-approved drug compound library and identified Anagrelide (ANA), a known...
We performed a drug repurposing screening of a US Food and Drug Administration (FDA)-approved drug compound library and identified Anagrelide (ANA), a known phosphodiesterase 3A (PDE3A) inhibitor, that selectively and potently inhibited the growth of cancer cells. However, inactivation of PDE3A or knocking-down its gene expression did not inhibit cancer cell growth. It was the interaction of ANA with PDE3A that created a new function of PDE3A to alter the activities of another unknown function protein SLFN12 to cause the inhibition of cancer cell growth. The expressions of both PDE3A and SLFN12 were required for ANA to inhibit cancer cell growth. Depletion of PDE3A or SLFN12 led to ANA resistance. Furthermore, the effects of ANA on different cancer cells were different depending on the expression levels of PDE3A and SLFN12, causing G0/G1 cell cycle arrest in the cells expressing lower levels of SLFN12, but apoptosis in the cells expressing higher levels of the two proteins. Further investigation into the molecular mechanisms of the ANA-induced cell cycle arrest and apoptosis identified a set of cell cycle and apoptosis-related genes whose expressions were altered by ANA treatment. ANA also synergized with the cell death-inducing cytokines IFN-α, IFN-γ, TNF-α, or TRAIL, which regulated the same set of genes as ANA did, to induce apoptosis of the cancer cells. Our study uncovered new activities, functions, and mechanisms of ANA and SLFN12 and provided a diagnosis method to precisely use ANA as an anti-cancer drug. It also revealed PDE3A and SLFN12 as new anti-cancer drug targets for developing novel anti-cancer therapies.
PubMed: 31598394
DOI: No ID Found -
Haematologica May 2020
Topics: Cell Cycle; Cell Differentiation; Humans; Induced Pluripotent Stem Cells; Megakaryocyte Progenitor Cells; Megakaryocytes; Quinazolines
PubMed: 31488559
DOI: 10.3324/haematol.2018.214841 -
BMJ Case Reports Jul 2019Essential thrombocythaemia (ET) is characterised by elevated platelet count by a clonal stem cell disorder of megakaryocytes. Although thrombosis is a common...
Essential thrombocythaemia (ET) is characterised by elevated platelet count by a clonal stem cell disorder of megakaryocytes. Although thrombosis is a common complication of ET, splenic infarction (SI) is extremely rare. Here, we present the case of a 31-year-old Japanese man who presented with sudden-onset severe pain at the left hypochondrium on the day before admission. Enhanced abdominal CT revealed SI. The laboratory test results revealed a normal platelet count (439×10/L). Subsequently, the patient was diagnosed with ET because the platelet count gradually increased to 50.0×10/μL, and mutation was identified. Accordingly, low-dose aspirin was initiated, and no thrombotic episode occurred. Nevertheless, 6 months postdischarge, the platelet count gradually increased to >650 × 10/L, and anagrelide was initiated. This case demonstrates an unusual complication of acute SI due to ET under the rare situation of the normal platelet count.
Topics: Acute Disease; Adult; Humans; Male; Platelet Count; Splenic Infarction; Thrombocythemia, Essential
PubMed: 31272993
DOI: 10.1136/bcr-2019-229387 -
Surgical Case Reports Jun 2019Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by thrombocytosis and a propensity for both thrombotic and hemorrhagic events. ET rarely...
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.
PubMed: 31227949
DOI: 10.1186/s40792-019-0660-3 -
European Journal of Haematology Aug 2019This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy-naïve essential thrombocythemia (ET) patients in a real-world...
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 × 10 /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.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mutation; Platelet Aggregation Inhibitors; Platelet Count; Quinazolines; Risk Factors; Thrombocythemia, Essential; Treatment Outcome; Young Adult
PubMed: 31107982
DOI: 10.1111/ejh.13265 -
British Journal of Haematology May 2019Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing... (Comparative Study)
Comparative Study Randomized Controlled Trial
A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia - the TEAM-ET 2·0 trial.
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 × 10 /l (95% confidence interval (CI) 707-936 × 10 /l) and 797 × 10 /l (95% CI 708-883 × 10 /l) for A-PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 10 /l for A-PR (95% CI 254-311) and 305 × 10 /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.
Topics: Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Compounding; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Quality of Life; Quinazolines; Thrombocythemia, Essential; Treatment Outcome
PubMed: 30919941
DOI: 10.1111/bjh.15824 -
Leukemia Research Nov 2018EXELS, a post-marketing observational study, is the largest prospective study of high-risk essential thrombocythemia (ET) patients, with an observation time of 5 years.... (Clinical Trial)
Clinical Trial Observational Study
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).
Topics: Adult; Aged; Aged, 80 and over; Cell Transformation, Neoplastic; Female; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasms, Second Primary; Quinazolines; Thrombocythemia, Essential
PubMed: 30368038
DOI: 10.1016/j.leukres.2018.10.006 -
American Journal of Hematology Jan 2019First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study;... (Comparative Study)
Comparative Study
First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide. Whether or not anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Marrow; Disease Progression; Disease-Free Survival; Drug Approval; Female; Fibrosis; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mortality; Platelet Aggregation Inhibitors; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Proportional Hazards Models; Quinazolines; Retrospective Studies; Severity of Illness Index; Thrombocythemia, Essential; Thrombosis; Treatment Outcome; Young Adult
PubMed: 30252953
DOI: 10.1002/ajh.25294 -
Experimental Hematology & Oncology 2018Patients with polycythemia vera (PV) have a higher mortality risk compared with the general population, primarily driven by cardiovascular disease, thrombotic events...
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.
PubMed: 30002948
DOI: 10.1186/s40164-018-0107-8