UNASSIGNED: In this study, we investigated the effects of calreticulin (CALR) and JAK2V617F mutational status on clinical course and disease outcomes in Turkish patients with essential thrombocythemia (ET).
UNASSIGNED: Seventeen centers from Türkiye participated in the study and CALR- and JAK2V617F-mutated ET patients were evaluated retrospectively.
UNASSIGNED: A total of 302 patients were included, of whom 203 (67.2%) and 99 (32.8%) were JAK2V617F- and CALR-positive, respectively. CALR-mutated patients were significantly younger (51 years vs. 57.5 years, p=0.03), with higher median platelet counts (987x109/L vs. 709x109/L, p<0.001) and lower median hemoglobin levels (13.1 g/dL vs. 14.1 g/dL, p<0.001) compared to JAK2V617F-mutated patients. Thromboembolic events (TEEs) occurred in 54 patients (17.9%), 77.8% of which were arterial. Compared to CALR mutation, JAK2V617F was associated with a higher risk of thrombosis (8.1% vs. 22.7%, p=0.002). Rates of transformation to myelofibrosis (MF) and leukemia were 4% and 0.7%, respectively, and these rates were comparable between JAK2V617F- and CALR-mutated cases. The estimated overall survival (OS) and MF-free survival of the entire cohort were 265.1 months and 235.7 months, respectively. OS and MF-free survival durations were similar between JAK2V617F- and CALR-mutated patients. Thrombosis-free survival (TFS) was superior in CALR-mutated patients compared to JAK2V617F-positive patients (5-year TFS: 90% vs. 71%, respectively; p=0.001). Age at diagnosis was an independent factor affecting the incidence of TEEs.
UNASSIGNED: In our ET cohort, CALR mutations resulted in higher platelet counts and lower hemoglobin levels than JAK2V617F and were associated with younger age at diagnosis. JAK2V617F was strongly associated with thrombosis and worse TFS. Hydroxyurea was the most preferred cytoreductive agent for patients with high thrombosis risk.
UNASSIGNED: Bu çalışmada Türk esansiyel trombositemi (ET) hastalarında CALR ve JAK2V617F mutasyon durumunun klinik seyir ve hastalık sonuçlarına etkilerini araştırdık.
UNASSIGNED: Çalışmaya Türkiye’den 17 merkez katılmış olup, CALR ve JAK2V617F mutasyonu pozitif olan ET hastaları geriye dönük olarak değerlendirilmiştir.
UNASSIGNED: Çalışmaya toplam 302 hasta dahil edildi. Bunların 203’ü (%67,2) JAK2V617F ve 99’u (%32,8) CALR pozitifti. CALR mutasyonlu hastalar JAK2V617F pozitif olanlara göre daha gençti (sırasıyla; 51 yaş, 57,5 yaş, p=0,03), daha yüksek ortanca trombosit sayısına (sırasıyla; 987x109/L, 709x109/L, p<0,001) ve daha düşük ortanca hemoglobin düzeylerine (sırasıyla; 13,1 g/dL, 14,1 g/dL, p<0,001) sahipti. Tromboembolik olaylar (TEO) 54 hastada (%17,9) meydana geldi ve bunların %77,8’i arteriyeldi. CALR mutasyonu ile karşılaştırıldığında JAK2V617F daha yüksek tromboz riski ile ilişkiliydi (%8,1’e karşı %22,7, p=0,002). Miyelofibroz (MF) ve lösemiye dönüşüm oranları sırasıyla %4 ve %0,7 idi ve bu oranlar JAK2V617F ve CALR mutasyonlu olgular arasında benzerdi. Tüm kohortta tahmini toplam sağkalım (OS) ve MF’siz sağkalım sırasıyla 265,1 ay ve 235,7 aydı. JAK2V617F ve CALR mutasyonlu hastalar arasında OS ve MF’siz sağkalım benzerdi. CALR mutasyonlu vakalarda trombozsuz sağkalım (TFS), JAK2V617F pozitif hastalara göre daha üstündü (5 yıllık TFS sırasıyla; %90, %71 [p=0,001]). Tanı yaşı TEO insidansını etkileyen bağımsız bir faktördü.
UNASSIGNED: ET kohortumuzda CALR mutasyonları, JAK2V617F’ye göre daha yüksek trombosit sayısı, daha düşük hemoglobin düzeyi ve tanı anında daha genç yaşla ilişki bulundu. JAK2V617F, tromboz ve daha kötü TFS ile güçlü bir şekilde ilişkiliydi. Hidroksiüre yüksek tromboz riski olan hastalarda en çok tercih edilen sitoredüktif ilaçtı.

UNASSIGNED: Essential thrombocythemia (ET), a myeloproliferative neoplasm (MPN), has a substantial risk of evolving into post-essential thrombocythemia myelofibrosis (post-ET MF). This study aims to establish a prediction nomogram for early prediction of post-ET MF in ET patients.
UNASSIGNED: The training cohort comprised 558 patients from 8 haematology centres between January 1, 2010, and May 1, 2023, while the external validation cohort consisted of 165 patients from 6 additional haematology centres between January 1, 2010, and May 1, 2023. Univariable and multivariable Cox regression analysis was performed to identified independent risk factors and establish a nomogram to predict the post-ET MF free survival. Both bias-corrected area under the curve (AUC), calibration curves and concordance index (C-index) were employed to assess the predictive accuracy of the nomogram.
UNASSIGNED: Multivariate Cox regression demonstrated that elevated red blood cell distribution width (RDW), elevated levels of lactate dehydrogenase (LDH) and the level of haemoglobin (Hb), a history of smoking and the presence of splenomegaly were independent risk factors for post-ET MF. The C-index displayed of the training and validation cohorts were 0.877 and 0.853. The 5 years, 10 years AUC values in training and external validation cohorts were 0.948, 0.769 and 0.978, 0.804 respectively. Bias-corrected curve is close to the ideal curve and revealed a strong consistency between actual observation and prediction.
UNASSIGNED: We developed a nomogram capable of predicting the post-ET MF free survival probability at 5 years and 10 years in ET patients. This tool helps doctors identify patients who need close monitoring and appropriate counselling.
UNASSIGNED: This research was funded by the Key R&D Program of Zhejiang (No. 2022C03137); the Public Technology Application Research Program of Zhejiang, China (No. LGF21H080003); and the Zhejiang Medical Association Clinical Medical Research special fund project (No. 2022ZYC-D09).

UNASSIGNED: In polycythemia vera (PV) patients undergoing phlebotomy, iron deficiency (ID) may develop. ID has been linked to restless legs syndrome (RLS), and in one study, 29.6% of PV patients had RLS. We aimed to evaluate the frequency of RLS in PV and to evaluate factors that might play a role in RLS development among PV and essential thrombocythemia (ET) patients.
UNASSIGNED: We consecutively included PV cases as the patient group, and ET and ID patients and healthy subjects (HSs) were included as controls. Those with conditions that could lead to RLS were excluded. All subjects were questioned according to the diagnostic criteria of the International Restless Legs Syndrome Study Group.
UNASSIGNED: Twenty-seven PV, 23 ET, and 22 ID patients and 23 HSs were included. RLS was detected in 25.9%, 34.8%, and 45.5% of PV, ET, and ID patients, respectively. None of the HSs had RLS. In univariate analysis, interferon-α and anagrelide use, magnesium levels, and the Leeds assessment of neuropathic symptoms and signs (LANSS) scores had a significant impact on RLS in PV and ET patients (p = 0.014, p = 0.032, p = 0.036, and p = 0.003, respectively).
UNASSIGNED: RLS was more common among PV and ET patients than HSs, which was irrespective to the iron status. RLS was more frequent in ET patients than that observed in PV cases, indicating that ID may not be the only causative factor for RLS development in PV. Further prospective studies are needed to determine the prevalence and risk factors of RLS developing in PV and ET.

Rationale: Precapillary pulmonary hypertension (PH) is a rare and largely unrecognized complication of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). Objectives: To describe characteristics and outcomes of MPN-associated PH. Methods: We report clinical, functional, and hemodynamic characteristics, classification, and outcomes of patients with PV, ET, or primary MF in the French PH registry. Measurements and Main Results: Ninety patients with MPN (42 PV, 35 ET, 13 primary MF) presented with precapillary PH with severe hemodynamic impairment, with a median mean pulmonary arterial pressure and pulmonary vascular resistance of 42 mm Hg and 6.7 Wood units, respectively, and impaired clinical conditions, with 71% in New York Heart Association functional classes III/IV and having a median 6-minute-walk distance of 310 m. Half of the patients were diagnosed with chronic thromboembolic PH (CTEPH); the other half were considered to have group 5 PH. MF was preferentially associated with group 5 PH, whereas PV and ET were generally related to CTEPH. Proximal lesions were diagnosed in half of the patients with CTEPH. Thromboendarterectomy was performed in 18 selected patients with high risk of complications (5 early deaths). Overall survival at 1, 3, and 5 years was 67%, 50%, and 34% in group 5 PH and 81%, 66%, and 42% in CTEPH, respectively. Conclusions: PH is a life-threatening condition potentially occurring in MPN. There are multiple mechanisms, with equal diagnoses of CTEPH and group 5 PH. Physicians should be aware that PH strongly affects the burden of patients with MPN, especially in group 5 PH, with unknown pathophysiological mechanisms.

BACKGROUND: The management to reduce risk of thromboembolic complications in polycythemia vera and essential thrombocythemia are well established, but for other conditions with elevated hemoglobin, hematocrit, or platelets there are no consensus regarding treatment and follow up.
OBJECTIVE: To assess frequency of elevated blood values in patients with thromboembolic event, how many of these should be investigated further regarding myeloproliferative neoplasm and if the risk of recurrent event is depending on underlying condition.
METHODS: Retrospective cohort study of 3931 adult patients in the county of Norrbotten, Sweden, with thromboembolism during 2017 and 2018.
RESULTS: Of the 3931 patients, 1195 had either elevated Hb, HCT, or platelets fulfilling the 2016 revised WHO criteria for PV and ET, and out of these 411 should be evaluated regarding underlying myeloproliferative neoplasms. Unexplained thrombocytosis and secondary erythrocytosis were associated with the highest rate of recurrent event as well as the most inferior restricted mean survival time.
CONCLUSIONS: Elevated blood values are common in patients with thromboembolic event and the high risk of recurrent event and inferior restricted mean survival time in patients with unexplained thrombocytosis and secondary erythrocytosis implicates the importance of finding and managing the underlying condition.

BACKGROUND: Thrombosis is a major complication of essential thrombocythemia (ET). There are three well-known prediction models for thrombotic risk in ET patients. However, only few external validation studies for the performance of these models in Asian populations have been conducted. Thus, we aimed to evaluate the performance of these models for predicting the risk of thrombosis in Thai patients with ET.
METHODS: We retrospectively evaluated the clinical characteristics and thrombotic risk of 149 Thai ET patients in a university hospital in Southern Thailand between 2002 and 2019. Thrombotic risk variables were evaluated using Cox proportional hazard regression. The Brier score, calibration plot, and Harrel concordance index (C-index) were used to evaluate the performance of the three models.
RESULTS: With a median follow-up of 5.2 years, there were a total of 28 thrombotic events in 26 patients. Age > 60 years was a significant prognostic factor for thrombosis in the multivariate Cox regression analysis. The Brier scores were 0.251, 0.273, and 0.276 in the conventional, IPSET-thrombosis, and revised IPSET-thrombosis models, respectively. The conventional model had optimal calibration and good discrimination (C-index, 0.67; 95%CI:0.55-0.79). The IPSET thrombosis (C-index 0.33; 95%CI:0.20-0.49) and revised IPSET thrombosis (C-index 0.31; 95%CI:0.18-0.44) models showed poor discrimination.
CONCLUSIONS: The conventional model, which is based on age and history of thrombosis, is the best model to predict thrombotic risk in Thai ET patients. Further studies with a larger number of patients with thrombotic events are needed to validate the IPSET-thrombosis and revised IPSET-thrombosis models.

As the discussion of first-line anagrelide treatment is ongoing, we aimed to prospectively examine the efficacy and safety of anagrelide in cytoreduction therapy-naïve high risk essential thrombocythemia (ET) patients in Korea. Seventy patients from 12 centers were treated with anagrelide monotherapy for up to 8 weeks, followed up until 24 months. At week 8, 50.0% of the patients were able to achieve platelet < 600 x 109/L, and by 12 months, 55/70 (78.6%) patients stayed on anagrelide, and 40.0% patients showed platelet normalization. 14 patients required additional hydroxyurea (HU) for cytoreduction. The median daily dose of needed HU was 500mg (range 250mg - 1500mg). The efficacy was independent of the somatic mutation status. There were 4 thromboembolic events and 7 bleeding events during the follow-up period. The most common adverse events associated with anagrelide use were headache, followed by palpitation/chest discomfort, edema and generalized weakness/fatigue. 7 patients wished to discontinue anagrelide treatment due to adverse events (3 due to headache; 2 due to edema; 1 due to palpitation and 1 due to skin eruption). All in all, first-line anagrelide treatment showed a favorable response with tolerable safety profiles regardless of somatic mutation status.

Objective Thrombocytosis can occur as a primary event accompanying hematological diseases or as a secondary event. Since the publication of the World Health Organization classification in 2008, thrombocytosis is now generally defined as a platelet count above 450×109/L. Furthermore, the discovery of driver-gene mutations in myeloproliferative neoplasms (MPNs) has simplified the diagnostic approach for thrombocytosis. To identify the causes of thrombocytosis using this new definition, we conducted a retrospective study. Methods We identified outpatients and inpatients aged 20 years or older with platelet counts >450×109/L in a half-year period at a single institute and analyzed the causes of thrombocytosis and associated clinical characteristics. Results Among 1,202 patients with thrombocytosis, 150 (12.5%) had primary and 999 (83.1%) had secondary thrombocytosis. Of these patients with primary thrombocytosis, 129 (86%) had at least 1 molecular marker indicative of MPNs. The major causes of secondary thrombocytosis were tissue injury (32.2%), infection (17.1%), chronic inflammatory disorders (11.7%) and iron deficiency anemia (11.1%). The median platelet count and the incidence of thrombosis were significantly higher in patients with primary thrombocytosis than in those with secondary thrombocytosis. Conclusion Thrombocytosis mainly occurs as a secondary event; however, it is important to determine the cause of and prevent thrombosis, particularly in cases of primary thrombocytosis.

The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) is an ongoing, noninterventional study assessing clinical characteristics and patient-reported outcomes (PROs) of patients with myelofibrosis (MF) or essential thrombocythemia (ET). This analysis assessed PROs at enrollment; symptom burden and quality of life (QoL), work productivity, and activity were assessed using validated questionnaires in patients with low- or intermediate-1-risk (age-alone) MF, or high- or low-risk ET (receiving ET-directed therapy) at enrollment. In MF and ET cohorts, fatigue had highest mean symptom score. Women had higher mean total symptom scores (TSS), mean symptom scores, and reduced QoL versus men. In patients with MF, mean TSS and symptom scores were similar between risk groups. Patients with low-risk ET had higher mean TSS and symptom scores than patients with high-risk ET. In conclusion, patients with lower risk MF and low- or high-risk ET experience significant symptom burden affecting QoL and ability to work.

Patients diagnosed with high-risk essential thrombocythemia (ET) have limited treatment options to reduce the risk of thrombosis and lessen the progression of the disease by targeting the molecular source. Hydroxyurea is the recommended treatment, but many patients experience resistance or intolerance. Anagrelide is an approved second-line option for ET, but concerns of a higher frequency of disease transformation may affect its role as a suitable long-term option. Interferons have been evaluated in myeloproliferative neoplasms for over 30 years, but early formulations had safety and tolerability issues. SURPASS-ET (NCT04285086) is a phase III, open-label, multicenter, global, randomized, active-controlled trial that will evaluate the safety, efficacy, tolerability and pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide as second-line therapy in high-risk ET.
Essential thrombocythemia (ET) is a condition characterized by having more platelets than normal. The high number of platelets increases the risk of a life-threatening blood clot and/or bleeding. Patients with ET and at a high risk for these events are usually treated first with hydroxyurea (HU), but some patients do not respond properly or may develop significant side effects. Anagrelide is an approved medication used in patients who do not respond to HU. Ropeginterferon alfa-2b is a disease-specific, long-acting interferon with a good safety profile approved in polycythemia vera, another type of myeloproliferative neoplasm. The SURPASS-ET clinical trial will evaluate the safety, efficacy, tolerability and pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide in patients with ET who are resistant or cannot tolerate HU. Clinical Trial Registration: NCT04285086 (ClinicalTrials.gov).