scholarly journals Management of thrombocythemia

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 227 ◽  
Author(s):  
Krisstina Gowin ◽  
Ruben Mesa

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.

1995 ◽  
Vol 74 (05) ◽  
pp. 1225-1230 ◽  
Author(s):  
Bianca Rocca ◽  
Giovanni Ciabattoni ◽  
Raffaele Tartaglione ◽  
Sergio Cortelazzo ◽  
Tiziano Barbui ◽  
...  

SummaryIn order to investigate the in vivo thromboxane (TX) biosynthesis in essential thromboeythemia (ET), we measured the urinary exeretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p <0.001) in thrombocythemic patients (4,063 ± 3,408 pg/mg creatinine; mean ± SD) than in controls (504 ± 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 >2 SD above the control mean. Patients with platelet number <1,000 × 109/1 (n = 25) had significantly higher (p <0.05) 11 -dehydro-TXB2 excretion than patients with higher platelet count (4,765 ± 3,870 pg/mg creatinine, n = 25, versus 2,279 ± 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging >55 was significantly higher than in the younger group (4,784 ± 3,948 pg/mg creatinine, n = 24, versus 2,405 ± 1,885 pg/mg creatinine, n = 16, p <0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p <0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p <0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age >55 and platelet count <1,000 × 1099/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo;2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.


2015 ◽  
Vol 8 ◽  
pp. CCRep.S22820 ◽  
Author(s):  
Mohamed A. Yassin ◽  
Samah Kohla ◽  
Ahmad Al-Sabbagh ◽  
Ashraf T. Soliman ◽  
Anil Yousif ◽  
...  

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that represents a diagnostic dilemma for both clinicians and pathologists. Because this disease entity is very rare, and because its diagnosis is by exclusion, it is important for clinical hematologists and hemato-pathologists to be familiar with CNL when approaching patients with MPNs and persistent neutrophilia. A woman in her 40s who was incidentally found to have leukocytosis was referred to the hematology service at the National Center for Cancer Care and Research for evaluation. Complete blood count revealed hyperleukocytosis with predominant neutrophilia. Peripheral blood and flow cytometry did not show any evidence of lymphoproliferative disorder or myeloblasts. Bone marrow aspirate and biopsy revealed a hypercellular marrow with myeloid hyperplasia. Cytogenetics revealed normal karyotype. Tests for both Janus kinase mutation JAK2 V617F and rearrangement of the genes BCR–ABL1, platelet-derived growth factor receptor-α (PDGFRα), PDGFRβ, and fibroblast growth factor receptor-1 (FGFR1) were negative. Thereafter, the diagnosis of CNL was reached. She was treated with pegylated interferon alpha-2a, with very good hematological response. To the best of our knowledge, this is the first case of CNL reported among the Arab population.


Leukemia ◽  
2020 ◽  
Vol 35 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Moshe Talpaz ◽  
Jean-Jacques Kiladjian

AbstractMyeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) is characterized by cytopenias, marrow fibrosis, constitutional symptoms, extramedullary hematopoiesis, splenomegaly, and shortened survival. Constitutive activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in MF leads to cell proliferation, inhibition of cell death, and clonal expansion of myeloproliferative malignant cells. Fedratinib is a selective oral JAK2 inhibitor recently approved in the United States for treatment of adult patients with intermediate-2 or high-risk MF. In mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT5, increased survival, and improved MF-associated disease features, including reduction of white blood cell counts, hematocrit, splenomegaly, and fibrosis. Fedratinib exerts off-target inhibitory activity against bromodomain-containing protein 4 (BRD4); combination JAK/STAT and BRD4 inhibition was shown to synergistically block NF-kB hyperactivation and inflammatory cytokine production, attenuating disease burden and reversing bone marrow fibrosis in animal models of MPNs. In patients, fedratinib is rapidly absorbed and dosed once daily (effective half-life 41 h). Fedratinib showed robust clinical activity in JAK-inhibitor-naïve patients and in patients with MF who were relapsed, refractory, or intolerant to prior ruxolitinib therapy. Fedratinib is effective regardless of JAK2 mutation status. Onset of spleen and symptom responses are typically seen within the first 1–2 months of treatment. The most common adverse events (AEs) with fedratinib are grades 1–2 gastrointestinal events, which are most frequent during early treatment and decrease over time. Treatment discontinuation due to hematologic AEs in clinical trials was uncommon (~3%). Suspected cases of Wernicke’s encephalopathy were reported during fedratinib trials in ~1% of patients; thiamine levels should be monitored before and during fedratinib treatment as medically indicated. Phase III trials are ongoing to assess fedratinib effects on long-term safety, efficacy, and overall survival. The recent approval of fedratinib provides a much-needed addition to the limited therapeutic options available for patients with MF.


2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Rory M. Shallis ◽  
Nikolai A. Podoltsev

AbstractPolycythemia vera (PV) and essential thrombocythemia (ET) are both driven by JAK-STAT pathway activation and consequently much of the recent research efforts to improve the management and outcomes of patients with these neoplasms have centered around inhibition of this pathway. In addition to newer JAK inhibitors and improved interferons, promising novel agents exploiting a growing understanding of PV and ET pathogenesis and disease evolution mechanisms are being developed. These agents may modify the disease course in addition to cytoreduction. Histone deacetylase, MDM2 and telomerase inhibitors in patients with PV/ET have demonstrated clinically efficacy and serve as chief examples. Hepcidin mimetics, limiting iron availability to red blood cell precursors, offer an exciting alternative to therapeutic phlebotomy and have the potential to revolutionize management for patients with PV. Many of these newer agents are found to improve hematologic parameters and symptom burden, but their role in thrombotic risk reduction and disease progression control is currently unknown. The results of larger, randomized studies to confirm the early efficacy signals observed in phase 1/2 trials are eagerly awaited.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2904-2904
Author(s):  
Ruben A. Mesa ◽  
Jerome Rey ◽  
Ayalew Tefferi ◽  
Joyce Niblack ◽  
Pascal Lenain ◽  
...  

Abstract Abstract 2904 Poster Board II-880 Background: The myeloproliferative neoplasm (MPN) of essential thrombocythemia (ET) can cause a constellation of symptoms in afflicted patients either from direct consequence of vascular and circulatory events (i.e. thrombosis, hemorrhage, erythromelalgia), or more indirectly as a consequence of the myeloproliferation itself (fatigue, pruritus, constitutional symptoms). These latter symptoms, of significant importance to patients, are more challenging for physicians to interpret given they are self reported by patients and influenced by many factors including culture. We sought to identify the concordance of self reported fatigue, and impact on daily life in patients with ET between 2 large and independently administered studies performed in the USA and France, respectively. Methods: Two large, separate, trials of symptomatic burden were used for the analysis. The first an internet based trial originating from the USA of self reported symptoms across the spectrum of patients with MPNs (Mesa et. al. Cancer 2007), the data included in this analysis a previously unreported subset analysis on patients from the USA with ET. The second trial a multi-centre, prospective questionnaire based analysis including many aspects of the impact of ET upon patients in France including fatigue and daily life. Key areas of overlap between these 2 trials were analyzed to assess whether any substantive differences in the impact of ET on daily life or fatigue between these 2 patient groups. Results: PATIENTS: A total of 447 patients with ET were included in the analysis (222 from the French Series (median age 57.8 years (range 19-90), 225 from the USA Series (median age 53 years (range 16-82)). In the 2 series, respectively, 78%, and 77% received cytoreductive therapy, and 16%, and 22% had a history of a vascular event. FATIGUE AND IMPACT ON DAILY LIFE: Fatigue was a self reported problem across the majority respondents in this analysis 287/447 (64%) self reporting fatigue as a problem. The prevalence of fatigue did not vary significantly between the 2 countries (158/225 (70.2%) - USA, - 129/222 (58%) – France). In contrast, in the French study where parallel questionnaires were completed by the patients and their hematologists, the doctor considered fatigue as a significant symptom in only 17% of patients. Additionally the majority of respondents felt the ET was the reason, at least partially, for their fatigue (316/447; 71%) again with no significant difference amongst the regions (69% USA, 73% France). Self reported metrics such as decreased libido (25% USA, 24% France) demonstrated remarkable similarity across cultural and geographic differences. Finally when asked directly whether ET negatively impacted their daily life, 46% of US patients responded in the affirmative (ranging from modest to severe impact). In France), the patients reported impact of ET on their: professional life (37%), hobbies (24%) and mood (74%). Conclusions: The symptomatic impact of a diagnosis of ET upon afflicted patients is significant, present in a majority of patients, and surprisingly consistent across 2 different cultural and geographic regions. The deep difference between patient's and doctors' consideration of fatigue as a meaningful symptom underlines the need for objective symptom assessment tools in MPN. (The French portion of this study was sponsored by Shire, Inc.) Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 110-110 ◽  
Author(s):  
Agnes Charpentier ◽  
Nathalie Cambier ◽  
Anne Bauters ◽  
Nathalie Trillot ◽  
Matthieu Wemeau ◽  
...  

Abstract Rationale: Essential Thrombocythemia (ET) is a Philadelphia-negative myeloproliferative neoplasm characterized by an increased risk of thrombosis. Previous reports suggest a role for microparticles (MP) in the pathogenesis of thrombosis in ET. MPs are small plasma membrane vesicles bearing potent procoagulant proteins and phospholipids. They are released into the circulation by various blood and endothelial cells after cellular activation and/or apoptosis. The recently described somatic calreticulin (CALR) exon 9 mutations in almost 20% of ET defines a lower-risk thrombosis ET subtype. We extensively studied phenotype and procoagulant activity of plasma MPs in order to assess MP contribution to the thrombotic risk in CALR versus JAK2 (V617F) mutated ET patients. Patients and methods: We analyzed MP count, phenotype and procoagulant activity in 45 JAK2 V617F+ and 15 CALR+ consecutive and newly diagnosed ET patients in accordance to WHO criteria recruited between november 2010 and april 2013. After given informed consent, blood samples were obtained in all patients before initiating any cytoreductive therapy. Pre-analytical and testing procedures complied with the recommendations of the ISTH Standardization Sub-Committee and each test was performed in duplicate . Using flow cytometry (FC500 flow-cytometer, Beckman-Coulter™), MPs were characterized and measured in platelet-free plasma samples. MPs were characterized by their size and co-expression of bound Annexin V and the following cell-specific monoclonal antibodies: CD41 (Platelet-MP, PMP), CD235a (Red cell-MP, RMP), CD14 (Monocytes-MP, MoMP), CD11b (Granulocytes-MP, GMP), CD144 (Endothelial-MP, EMP), CD62P and CD41 (P-Selectin+ PMP), CD142 and CD41 (Tissue Factor (TF)+ PMP, TF+PMP). MP-associated procoagulant activity was also measured using a-thrombin generation assay (Zymuphen™ MP-activity). Statistical analysis was performed with SPSS software. Results are expressed as median [interquartile range]. Results: Patients characteristics: The platelet count (109/L) was higher in CALR+ than in JAK2+ patients (866 [666 – 918], 659 [571 – 807] respectively, p= 0.049), and all other clinical and hematological characteristics were also distributed in agreement with previous reports. Furthermore, CALR+ patients were preferentially distributed in the lower risk categories of the IPSET-thrombosis and IPSET-survival scores than in JAK2+ patients (p<0.00001 and p= 0.04 respectively). The main results are summarized in table 1. MP count and MP/Platelets ratio were significantly lower in CALR+ than in JAK2+ patients. PMP count, PMP percentage of all MPs and PMP/Platelets ratio were lower in CALR+ than in JAK2+ patients. Furthermore, CALR+ patients had lower PMP surface P-Selectin. MP-associated procoagulant activity/Platelets ratio was significantly lower in CALR+ than in JAK2+ patients. There were no significant differences in TF-carrying PMP or in other cell-derived MP (RMP, MoMP, GMP, EMP). Conclusion: Our results demonstrate a decreased in circulating procoagulant PMP in CALR+ ET-patients compared to JAK2+ patients and lower platelet activation in CALR+ ET patients as measured by P-Selectin expression on PMP. Thus, as CALR+ patients have lower thrombotic-risk according to the literature and the IPSET-survival and IPSET-thrombosis scores observed in our study, the lower level of procoagulant PMP could account, at least in part, for a lower thrombotic risk of CALR+ ET patients. Table 1 main results CALR + JAK2 V617F + p value MP (/µL) 3289 [1662-4240] 4961 [2697-6687] 0.04 MP/Platelets 3.6 [2.8-5.3] 6.9 [4.7-9.6] 0.01 PMP (/µL) 3100 [2068–3887] 5702 [3423-10257] 0.004 PMP/Platelets 3.38 [2.97–6.33] 7.55 [5.12–12.66] 0.002 % PMP 90 [84–92] 93 [90–96] 0.03 MP-activity(nM)/platelet 0.015 [0.008–0.028] 0.029 [0.019–0.041] 0.05 P-Selectin+ PMP (/µL) 195 [152-219] 747 [383-965] 0.001 RMP (/µL) 4 [1.7–8.2] 4 [2.5–9.7] ns MoMP (/µL) 43 [27–52] 74.5 [22–135] ns GMP (/µL) 31.5 [24–48] 30 [11–55] ns EMP (/µL) 99.4 [32–110] 95.6 [51–140] ns TF+ PMP (/µL) 22.3 [9.8–115] 27.1 [20.8–94.4] ns Disclosures No relevant conflicts of interest to declare.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7055-7055
Author(s):  
Ruben A. Mesa ◽  
Craig Zimmerman ◽  
Lih Lisa Kang ◽  
Albert Qin ◽  
Chungwei Lee ◽  
...  

7055 Background: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN), covering broad spectrum of clinical scenarios, from asymptomatic patients with only isolated high platelets to highly morbid patients in late stage disease. Due to heterogenous patient population, designing clinical studies in ET is difficult, and after anagrelide there was no new drug approval to treat ET during the past 15 years, thus, high unmet medical to treat patients with ET remains. Interferons alpha (IFNa) are known to have beneficial effects in MPN (Kiladjian et al, 2016). P1101 is a next generation monopegylated IFNa, developed specifically to treat MPNs, including ET. Methods: External published clinical data in ET were analyzed to design optimal clinical study. Proposed endpoints are meant to cover all relevant clinical aspects of ET, and suffice for a regulatory relevant pivotal clinical study. Results: Composite primary endpoint scale is based on modified ELN criteria. Short term study endpoints should have clinical meaningfulness at time of measurement but also predict the later outcomes. The scale consists of: normalization of platelets (<400 G/L) and leukocytes (<9.5 G/L); normalization in size or non-progression of palpable spleen; lack of major cardiovascular event during the observation period; and improvement of Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS). MPN-SAF TSS is a 10 items questionnaire, allowing concise, valid, and accurate assessment of MPN symptom burden over time (Emanuel et al, 2012). For TSS-10 score, to qualify for response, following rules were elaborated: 10 points or higher reduction for patients with baseline score of ≥20, for patients with baseline score 15-19 – 5 points reduction, baseline scores 10-14 – reduction below 10 points, and for TSS baseline score <10 – stay <10. Bone marrow analysis is not to be a mandatory test for assessment of overall benefit of therapy. Extensive genetic workup is planned to document any change in observed genetic and chromosomal abnormalities, including level of circulating mutant CALR. This would allow for objective evaluation of IFNa’s ability to modify the disease. Long term observation, going beyond the 12 month of initial observation, is planned. Conclusions: Authors conclude that proposed endpoint scale covers well all clinically relevant aspects of ET, in order to make clinically relevant conclusions on durable benefits and risks of P1101 therapy.


Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 171-182 ◽  
Author(s):  
Bianca Rocca ◽  
Alberto Tosetto ◽  
Silvia Betti ◽  
Denise Soldati ◽  
Giovanna Petrucci ◽  
...  

Abstract Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2–dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).


2020 ◽  
Vol 18 (9) ◽  
pp. 1279-1284
Author(s):  
Andrew T. Kuykendall ◽  
Rami Komrokji

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by clonal overproduction of platelets and an increased risk of thrombohemorrhagic complications. Patients are risk stratified by driver mutation, age, and thrombotic history and treated to reduce the risk of thrombotic and hemorrhagic events. The significance of platelet number as a risk factor or treatment goal is unclear. Despite the preponderance of data failing to demonstrate an association, there exists a pervasive belief that higher platelet counts correlate with an increased thrombotic risk. In fact, the association between thrombocytosis and bleeding is more clearly supported. Variability in regional consensus guidelines contributes to the uncertainty. This article reviews the data that shed light on the importance of platelet count in patients with ET.


2021 ◽  
Author(s):  
Abdulrahman Fadhl Al-Mashdali ◽  
Mohamed Yassin

Abstract Essential thrombocythemia (ET) is an uncommon myeloproliferative neoplasm (MPN). It is more commonly encountered in females; around 20% of them are below 40 years old. The optimal management of ET during pregnancy and after delivery is still not well established. Here, we report a case of a young lady with ET who developed a marked rebound in her platelet count two weeks after delivery. She was on Pegylated Interferon (PEG-IFN) alfa 2-a during pregnancy, but she had stopped it on her own one month before delivery. We resumed her therapy, and subsequently, her platelet count reduced dramatically within four weeks to the acceptable range. This case emphasizes the importance of platelet count follow-up after delivery and outlines the management approach in such cases.


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