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PurposeFedratinib (SAR302503, TG101348) is an orally administered Janus kinase (JAK) 2-selective inhibitor that is being developed for the treatment of patients with myelofibrosis (MF). The objectives of this analysis were to develop a population pharmacokinetic (PK) model to characterize fedratinib concentration-time profiles in patients with MF, polycythemia vera (PV) and essential thrombocythemia (ET) following oral fedratinib administration; and to investigate the effects of selected covariates on fedratinib PK parameters.MethodsNonlinear mixed effects modeling was employed in developing a population PK model for fedratinib. Intensive or sparse fedratinib concentration data collected in adult subjects with MF, PV or ET from six studies were pooled, and a total of 452 subjects and 3442 plasma concentration observations were included in the final model.ResultsFedratinib PK in patients with MF/PV/ET was adequately described by a two-compartment structural PK model with first-order absorption incorporating a lag time and first-order elimination. Following oral administration, fedratinib undergoes biphasic disposition and exhibits linear, time-invariant PK at doses of 200 mg and above. Compared to MF/ET patients, PV patients had higher apparent clearance (CL/F) and apparent central volume of distribution. Creatinine clearance was a statistically significant covariate on CL/F, and patients with mild and moderate renal impairment had 10% and 37% increases in fedratinib exposure as compared to patients with normal renal function. No clinically meaningful effect on fedratinib exposure was observed regarding age, body weight, sex, race and liver function.ConclusionsThese results should serve as the basis for dose adjustment of fedratinib for special populations.

Chronic myeloproliferative neoplasms are characterized by clonal myeloid expansion driven by activating mutations in the JAK2 pathway and chronic inflammation. The aim was to investigate the contribution of circulating inflammatory mediators to the abnormalities in the megakaryocytic lineage characteristic of MF and ET. Plasma samples from 30 MF and 28 ET patients were incubated with normal cord-blood CD34 + progenitors and megakaryo/thrombopoiesis was evaluated. MF plasma increased megakaryocyte output, which was attenuated in sequential samples from ruxolitinib-treated patients. JAK1/2, MAPK and NF-kB inhibitors reverted this effect, revealing the concomitant involvement of all three pathways. Elevated levels of circulating IL-1β and IL-6 correlated with megakaryocyte output, which was reverted by blocking antibodies, indicating this phenotype is partly driven by these inflammatory cytokines. Instead, ET plasma promoted enhanced proplatelet formation, which was coupled with increased NFE2 and Bcl-xL expression. Elevated levels of circulating RANTES correlated with ET plasma-induced proplatelet formation, which was partially reverted by RANTES receptor CCR5 antagonist Maraviroc, indicating RANTES is involved in this process. These findings indicate that, in addition to clonal mutations, extrinsic inflammatory mediators play a direct role in MF and ET megakaryocyte abnormalities. The distinct cytokine profile could potentially be useful for the development of targeted therapies.

Elevated levels of neutrophil extracellular traps (NETs) are associated with thrombotic risks, in particular, for patients with elevated platelet counts, such as those with essential thrombocythemia (ET). Here, the tendency for NETosis and neutrophil activity in such patients was assessed. A total of forty-one pediatric patients with elevated platelet counts diagnosed with ET (nine with CALR driver mutation, eleven with JAK2, thirteen triple-negative, and one dual-negative (TN)) or secondary thrombocytosis (five) were recruited. The tendency for NETosis was determined in a leucocyte-rich blood plasma smear using immunofluorescence staining with antibodies against myeloperoxidase and elastase. Activity of neutrophils was assessed ex vivo in parallel-plate flow chambers. The mean level of NETosis in healthy volunteers was 2.7-6.7% (95% CI). Among the ET patients, there was no statistically significant difference in NETosis level between those with mutations in CALR (19-43%), JAK2 (22-58%), and TN ones (6-27%). Patients with secondary thrombocytosis also had an elevated level of NETosis (8-66%). The velocity of neutrophil chemotaxis was significantly increased in all patients, in particular for those with mutations in CALR. These data reveal a major shift in the neutrophil activity in ET and suggest that the immunomorphological techniques presented here may allow reproducible and widely available characterization of neutrophil status.

The current retrospective study evaluated clinical, genetic, and prognostic correlates of increased absolute basophil (ABC) and eosinophil (AEC) counts in polycythemia vera (PV; N  = 475) and essential thrombocythemia (ET; N  = 658). Median (range) ABC and AEC were 0.1 (0-3.2) and 0.3 (0-6.5) x 10 9 /L in PV and 0.07 (0-0.8) and 0.2 (0-1.4) x 10 9 /L in ET. In PV, ABC ≥ 0.1 × 10⁹/L was associated with palpable splenomegaly and increased AEC, leukocyte count, and platelet count while AEC ≥ 0.5 × 10⁹/L was associated with increased ABC and leukocyte count. In ET, ABC ≥ 0.1 × 10⁹/L was associated with increased AEC, leukocyte count, platelet count, and cardiovascular risk factors while AEC ≥ 0.5 × 10⁹/L correlated with ABC and increased leukocyte count; genetic associations were seen only in ET and included ABC ≥ 0.1 × 10⁹/L with triple-negative driver mutation status ( p  = 0.03). In PV, AEC did not correlate with overall (OS), leukemia-free (LFS), myelofibrosis-free (MFFS), arterial thrombosis-free (ATFS), or venous thrombosis-free (VTFS) survival; by contrast, ABC ≥ 0.1 × 10⁹/L was associated with longer ATFS ( p  = 0.03) while ABC ≥ 0.3 × 10⁹/L was associated with inferior LFS ( p  < 0.01) and MFFS ( p  < 0.01); the associations with LFS and MFFS were sustained during multivariable analysis. In ET, both ABC ≥ 0.1 × 10⁹/L and AEC ≥ 0.5 × 10⁹/L were independently associated with inferior OS but impact on LFS, MFFS, ATFS, or VTFS was not apparent. The results from the current study warrant additional studies to clarify the potential association between basophilia in PV and disease transformation into acute myeloid leukemia and myelofibrosis.

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPNs), often associated with mutations in JAK2 , CALR , and MPL . Differentiating PV from ET can be challenging in borderline cases, particularly when hemoglobin (Hb), hematocrit (Hct) and erythropoietin (EPO) values are inconclusive. Functional iron parameters and JAK2 variant allele frequency (VAF) may provide additional discriminatory value. To assess the diagnostic utility of transferrin saturation index (TSI), serum ferritin, EPO, and JAK2 VAF in distinguishing PV from ET, and to evaluate their association with mutational profiles. We conducted a retrospective, single-center study including 260 adult patients diagnosed with PV or ET between 2009 and 2024. Demographic, clinical, molecular, and laboratory parameters—including ferritin, TSI, EPO, Hb, Hct, and JAK2 VAF—were analyzed. Comparative and correlation analyses were performed using appropriate statistical tests. Compared to ET, patients with PV had significantly lower ferritin (median: 35.65 vs. 95.05 ng/mL), TSI (12.9% vs. 21.64%), and EPO (2.23 vs. 6.11 mIU/mL), but higher Hb (17.7 vs. 14.3 g/dL) and Hct (54.6% vs. 43.0%) (all p < 0.001). TSI discriminated PV from ET better than ferritin (p < 0.001 vs. p = 0.128). Among JAK2-mutated cases, VAF was higher in PV than ET (median: 48% vs. 21%, p = 0.003). VAF correlated inversely with ferritin, TSI, and EPO, and positively with Hct. TSI and JAK2 VAF outperform ferritin as diagnostic markers to differentiate PV from ET. Integrating functional iron parameters with molecular data improves diagnostic accuracy, particularly in clinically ambiguous cases, and supports their inclusion in MPN diagnostic algorithms.

To assess the effects between MPL and JAK2V617F on the thrombosis risk and peripheral blood cell counts in patients with essential thrombocythemia (ET), we identified eligible studies from PubMed, Embase, and the Cochrane Library. Seven studies were ultimately included in this meta-analysis. All studies reported the peripheral blood cell counts of ET patients, and three of them reported the eligible thrombotic events. In comparing the effect of MPL versus JAK2V617F on thrombosis, 1257 ET patients (73 MPL + and 1184 JAK2V617F +) were included. MPL-positive (MPL +) ET patients had a higher risk of thrombosis than JAK2V617F-positive (JAK2V617F +) ET patients [RR = 1.80 (1.08–3.01), P = 0.025]. And 3453 ET patients (138 MPL + and 3315 JAK2V617F +) were included in the comparison of peripheral blood cell counts. Platelet counts of MPL + ET patients were higher than that of JAK2V617F + ET patients [WMD = 81.18 (31.77–130.60), P = 0.001]. MPL + ET patients had lower hemoglobin [WMD =  − 11.66 (− 14.32 to − 9.00), P = 0.000] and white blood cell counts [WMD =  − 1.01 (− 1.47 to − 0.56), P = 0.000] than JAK2V617F + ET patients. These findings indicate that the MPL mutation is a high-risk factor for thrombosis in ET patients, and it may be rational to include MPL mutation in the revised IPSET as a criterion for thrombosis prediction scores. And given the differences in peripheral blood, it is necessary to further study whether MPL + ET patients differ from JAK2V617F + ET patients in bleeding and survival.

C -Mannosyl tryptophan (CMW), a unique glycosylated amino acid, is considered to be produced by degradation of C -mannosylated proteins in living organism. Although protein C -mannosylation is involved in the folding and secretion of substrate proteins, the pathophysiological function in the hematological system is still unclear. This study aimed to assess CMW in the human hematological disorders. The serum CMW levels of 94 healthy Japanese workers were quantified using hydrophilic interaction liquid chromatography. Platelet count was positively correlated with serum CMW levels. The clinical significance of CMW in thrombocytosis of myeloproliferative neoplasms (T-MPN) including essential thrombocythemia (ET) were investigated. The serum CMW levels of the 34 patients with T-MPN who presented with thrombocytosis were significantly higher than those of the 52 patients with control who had other hematological disorders. In patients with T-MPN, serum CMW levels were inversely correlated with anemia, which was related to myelofibrosis (MF). Bone marrow biopsy samples were obtained from 18 patients with ET, and serum CMW levels were simultaneously measured. Twelve patients with bone marrow fibrosis had significantly higher CMW levels than 6 patients without bone marrow fibrosis. Collectively, these results suggested that CMW could be a novel biomarker to predict MF progression in T-MPN.

Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm that increases the risk of thrombosis. To diagnose this disease, the analysis of mutations in the Janus Kinase 2 (JAK2), thrombopoietin receptor (MPL), or calreticulin (CALR) gene is recommended. Disease poses diagnostic challenges due to overlapping mutations with other neoplasms and the presence of triple-negative cases. This study explores the potential of Raman spectroscopy combined with machine learning for ET diagnosis. We assessed two laser wavelengths (785, 1064 nm) to differentiate between ET patients and healthy controls. The PCR results indicate that approximately 50% of patients in our group have a mutation in the JAK2 gene, while only 5% of patients harbor a mutation in the ASXL1 gene. Additionally, only one patient had a mutation in the IDH1 and one had a mutation in IDH2 gene. Consequently, patients having no mutations were also observed in our group, making diagnosis challenging. Raman spectra at 1064 nm showed lower amide, polysaccharide, and lipid vibrations in ET patients, while 785 nm spectra indicated significant decreases in amide II and C-H lipid vibrations. Principal Component Analysis (PCA) confirmed that both wavelengths could distinguish ET from healthy subjects. Support Vector Machine (SVM) analysis revealed that the 800–1800 cm −1 range provided the highest diagnostic accuracy, with 89% for 785 nm and 72% for 1064 nm. These findings suggest that FT-Raman spectroscopy, paired with multivariate and machine learning analyses, offers a promising method for diagnosing ET with high accuracy by detecting specific molecular changes in serum. Principal Component Analysis (PCA) confirmed that both wavelengths could distinguish ET from healthy subjects. Support Vector Machine (SVM) analysis revealed that the 800–1800 cm −1 range provided the highest diagnostic accuracy, with 89% for 785 nm and 72% for 1064 nm. These findings suggest that FT-Raman spectroscopy, paired with multivariate and machine learning analyses, offers a promising method for diagnosing ET with high accuracy by detecting specific molecular changes in serum. Highlights Mutations in the JAK2 gene are present in 50% of patients, while mutations in the ASXL1, IDH1 , and IDH 2 genes are present in 5, 1.2 and 1.2% of patients. A strong correlation to the mutations in JAK2 , ASXL1 and IDH1 genes. The accuracy of the 785 nm laser was 89%, while that of the 1064 nm laser was 66%.

Polycythemia vera (PV) and Essential thrombcythemia (ET) are myeloproliferative neoplasms (MPNs) that can progress to secondary myelofibrosis, a complication associated with increased mortality. Circulating CD34-positive cells at diagnosis can be used to distinguish primary myelofibrosis from other MPNs with a threshold of 10/µL. In this study, we evaluate the interest of serial CD34-positive cell quantifications during the follow-up of MPNs. We retrospectively include 180 patients with MPN (90 ET, 55 PV and 35 myelofibrosis) with at least two measurements of circulating CD34-positive cells. CD34-positive cell count showed an AUC of 0.901 for the diagnosis of post-ET/PV myelofibrosis, with a sensitivity of 54.8%, a specificity of 99.5%, a PPV of 89.5% and a NPV of 96.3% for the threshold of 15 cells/µL. The decreased sensibility could be explained by an impact of cytoreductive treatments. Then we focused on primary and secondary myelofibrosis (MF) and found that patients achieving partial or complete response (per IWG-MRT criteria) had lower CD34-positive cell levels. Finally, CD34-positive cell levels had a prognostic impact on overall survival in MF, a count ≥ 100/µL is predictive of a higher risk of death (HR = 2.9 [1.5–5.9]), independently of DIPSS classification. In conclusion, monitoring of circulating CD34-positive cells is valuable for evaluating both disease progression and prognosis in MPN patients.

Essential thrombocythemia (ET) mainly affects the elderly, but can also develop in women of childbearing age. The risk of miscarriage and other complications during pregnancy in ET patients are reported to be higher than that compared to the general population. Therefore, management of pregnancy in ET patients requires special considerations. Several groups recommend interferon (IFN) therapy for ET patients with high-risk pregnancies, but currently no guidelines are available in Japan. We report the outcomes of nine ET patients with ten consecutive high-risk pregnancies. All patients were successfully managed with IFN-α during their pregnancies. All patients also received aspirin and switched to unfractionated heparin around 36 weeks of gestation. As for the seven pregnancies in which IFN-α was started after detection of pregnancy, median platelet counts decreased from 910 to 573 × 109/L after 2 months of IFN-α therapy, and median platelet counts at the time of delivery for all ten pregnancies was 361 × 109/L. All patients gave birth to healthy children. IFN-α was well tolerated, safe, and effective as a cytoreductive therapy for all patients. Although evidence is limited and the use of IFN is not approved in Japan, we suggest considering IFN therapy for high-risk ET pregnancies.