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To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting SVT at diagnosis (n = 69, median age 43 years) or during follow-up (n = 21, median age 46 years) to a sex- and age-matched control group of PV/ET without SVT (n = 165, median age 48 years). The majority of patients presenting with SVT at diagnosis were classified as myeloproliferative neoplasm with heterozygous JAK2 mutation (87% of cases vs. 69% in PV/ET control group, p < 0.05), characterized by low JAK2 allele burden and no high-risk mutations. Despite this lower molecular complexity, patients presenting with SVT showed a higher risk of death (HR 3.0, 95% CI 1.5-6.0, p = 0.003) and lower event-free survival (HR 3.0, 95% CI 1.9–4.8, p < 0.001) than age- and sex-matched PV/ET controls. In patients presenting with SVT, molecular high-risk was associated with increased risk of venous re-thrombosis (HR 5.8, 95% CI 1.4–24.0, p = 0.01). Patients developing SVT during follow-up were more frequently allocated in molecular high-risk than those with SVT at diagnosis (52% versus 13%, p < 0.05). In the whole cohort of patients, molecular classification identified PV/ET patients at higher risk of disease progression whereas DNMT3A/TET2/ASXL1 mutations were associated with higher risk of arterial thrombosis. In conclusion, clinical and molecular characteristics are different in PV/ET patients with SVT, depending on whether it occurs at diagnosis or at follow-up. Molecular characterization by NGS is useful for assessing the risk of thrombosis and disease progression in young patients with PV/ET. [ABSTRACT FROM AUTHOR]

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by excessive levels of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). Givinostat (ITF2357) is a potent histone‐deacetylase inhibitor that showed a good safety/efficacy profile in PV patients during phase I/II studies. A phase III clinical trial had been planned and an adaptive dosing protocol had been proposed where givinostat dose is iteratively adjusted every 28 days (one cycle) based on PLT, WBC, and HCT. As support, a simulation platform to evaluate and refine the proposed givinostat dose adjustment rules was developed. A population pharmacokinetic/pharmacodynamic model predicting the givinostat effects on PLT, WBC, and HCT in PV patients was developed and integrated with a control algorithm implementing the adaptive dosing protocol. Ten in silico trials in ten virtual PV patient populations were simulated 500 times. Considering an eight‐treatment cycle horizon, reducing/increasing the givinostat daily dose by 25 mg/day step resulted in a higher percentage of patients with a complete hematological response (CHR), that is, PLT ≤400 × 109/L, WBC ≤10 × 109/L, and HCT < 45% without phlebotomies in the last three cycles, and a lower percentage of patients with grade II toxicity events compared with 50 mg/day adjustment steps. After the eighth cycle, 85% of patients were predicted to receive a dose ≥100 mg/day and 40.90% (95% prediction interval = [34, 48.05]) to show a CHR. These results were confirmed at the end of 12th, 18th, and 24th cycles, showing a stability of the response between the eighth and 24th cycles. [ABSTRACT FROM AUTHOR]

Background and Objectives: Several polymorphisms have been described in various DNA repair genes. Nucleotide excision DNA repair (NER) detects defects of DNA molecules and corrects them to restore genome integrity. We hypothesized that the XPC, XPD, XPF, and XPG gene polymorphisms influence the appearance of myeloproliferative neoplasms (MPNs). Materials and Methods: We investigated the XPC 1496C>T (rs2228000, XPC Ala499Val), XPC 2920A>C (rs228001, XPC Lys939Gln), XPD 2251A>C (rs13181, XPD Lys751Gln), XPF-673C>T (rs3136038), XPF 11985A>G (rs254942), and XPG 3507G>C (rs17655, XPG Asp1104His) polymorphisms by polymerase chain reaction–restriction fragment length polymorphism analysis in 393 MPN patients [153 with polycythemia vera (PV), 201 with essential thrombocythemia (ET), and 39 with primary myelofibrosis (PMF)] and 323 healthy controls. Results: Overall, we found that variant genotypes of XPD 2251A>C were associated with an increased risk of MPN (OR = 1.54, 95% CI = 1.15–2.08, p = 0.004), while XPF-673C>T and XPF 11985A>G were associated with a decreased risk of developing MPN (OR = 0.56, 95% CI = 0.42–0.76, p < 0.001; and OR = 0.26, 95% CI = 0.19–0.37, p < 0.001, respectively). Conclusions: In light of our findings, XPD 2251A>C polymorphism was associated with the risk of developing MPN and XPF-673C>T and XPF 11985A>G single nucleotide polymorphisms (SNPs) may have a protective role for MPN, while XPC 1496C>T, XPC 2920A>C, and XPG 3507G>C polymorphisms do not represent risk factors in MPN development. [ABSTRACT FROM AUTHOR]

BACKGROUND Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P=0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.) [ABSTRACT FROM AUTHOR]

The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study, general practitioners, and outpatient clinics. We investigated NLR on mortality stratified by prevalent and incident MPN, essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), comorbidity burden (CCI-score), and the Triple-A risk score using hazard ratio (HR) and 95% confidence interval (95%CI). NLR 1–1.9 was the reference level. During a median follow-up of 11.2 years, 197,802 deaths were recorded. All-cause mortality increased for a stepwise increasing NLR with a HR (95%CI) for NLR ≥ 6 of 2.06(2.03–2.09) for the whole population and 2.93(2.44–3.50) in prevalent MPN. ET, PV, and MF had a HR (95%CI) for NLR ≥ 2 of 2.14(1.71–2.69), 2.19(1.89–2.54), and 2.31(1.91–2.80). Results were similar for incident MPN. Mortality was higher for stepwise increasing NLR and CCI-score(pinteraction < 2×10–16), with a HR for NLR ≥ 6 of 2.23(2.17–2.29), 4.10(4.01–4.20), and 7.69(7.50–7.89), for CCI-score 0, 1–2, or ≥3. The Triple-A risk score demonstrated alignment with NLR. Increasing NLR and comorbidity burden were associated with lower survival in individuals without MPN but were even worse in prevalent and incident MPN, ET, PV, and MF. [ABSTRACT FROM AUTHOR]

• Patients with MPN-related SVTs have high rates of re-thrombosis post-TIPS. • Re-thrombosis frequently occurred despite anticoagulation and re-intervention. • 86 % of patients had symptom resolution by one month post-procedure. [ABSTRACT FROM AUTHOR]

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. Despite a debated notion that red blood cells (RBCs) play a passive and minor role in thrombosis, there has been increasing evidence over the past decades that RBCs may play a biological and clinical role in PV and ET pathophysiology. This review summarizes the main mechanisms that suggest the involvement of PV and ET RBCs in thrombosis, including quantitative and qualitative RBC abnormalities reported in these pathologies. Among these abnormalities, we discuss increased RBC counts and hematocrit, that modulate blood rheology by increasing viscosity, as well as qualitative changes, such as deformability, aggregation, expression of adhesion proteins and phosphatidylserine and release of extracellular microvesicles. While the direct relationship between a high red cell count and thrombosis is well-known, the intrinsic defects of RBCs from PV and ET patients are new contributors that need to be investigated in depth in order to elucidate their role and pave the way for new therapeutical strategies. [ABSTRACT FROM AUTHOR]

In patients with low-risk polycythemia vera, exposure to low-dose Ropeginterferon alfa-2b (Ropeg) 100 µg every 2 weeks for 2 years was more effective than the standard treatment of therapeutic phlebotomy in maintaining target hematocrit (HCT) (< 45%) with a reduction in the need for phlebotomy without disease progression. In the present paper, we analyzed drug survival, defined as a surrogate measure of the efficacy, safety, adherence, and tolerability of Ropeg in patients followed up to 5 years. During the first 2 years, Ropeg and phlebotomy-only (Phl-O) were discontinued in 33% and 70% of patients, respectively, for lack of response (12 in the Ropeg arm vs. 34 in the Phl-O arm) or adverse events (6 vs. 0) and withdrawal of consent in (3 vs. 10). Thirty-six Ropeg responders continued the drug for up to 3 years, and the probability of drug survival after a median of 3.15 years was 59%. Notably, the primary composite endpoint was maintained in 97%, 94%, and 94% of patients still on drug at 3, 4, and 5 years, respectively, and 60% of cases were phlebotomy-free. Twenty-three of 63 Phl-O patients (37%) failed the primary endpoint and were crossed over to Ropeg; among the risk factors for this failure, the need for more than three bloodletting procedures in the first 6 months emerged as the most important determinant. In conclusion, to improve the effectiveness of Ropeg, we suggest increasing the dose and using it earlier driven by high phlebotomy need in the first 6 months post-diagnosis. [ABSTRACT FROM AUTHOR]

Objective: To assess the incidence of thrombotic events among patients with BCR::ABL1-negative myeloproliferative neoplasm (MPN) within a single center in Thailand. Materials and Methods: Conducted as a retrospective cohort study between 2008 and 2019, the present research focused on patients diagnosed with BCR::ABL1-negative MPN. Diagnoses were reviewed and reclassified based on the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2017). Data collected encompassed demographic details, comorbidities, investigation results, treatments, and outcomes. The primary focus was on thrombosis rates in arterial and venous sites. Secondary outcomes included the incidence of major bleeding, thrombosisfree survival (TFS), and overall survival (OS). Results: One hundred seventy-five patients participated in the present study and comprised of 46 patients (26.3%) with polycythemia vera (PV), 123 (70.3%) patients with essential thrombocythemia (ET), and six patients (3.4%) with primary myelofibrosis (PMF). Most patients were over 60 years old. The rate of overall thrombosis rate was 28.0%, with 43.5% in PV and 23.6% in ET. Common sites of thrombotic events included the cerebral artery at 16.6%, coronary artery at 6.3%, peripheral artery at 4.0% and venous thromboembolism at 3.4%. The overall bleeding event rate was 13.7%, with 70.8% classified as major bleeding. The all-cause mortality rate within the present cohort was 30.9%. TFS and OS stood 72.0% and 69.1%, respectively. Conclusion: Thrombosis emerged as a significant complication in patients with BCR::ABL1-negative MPN, affecting 28.0% of individuals in the present cohort. Arterial thromboses, particularly ischemic stroke and cardiovascular events, were the predominant occurrences. [ABSTRACT FROM AUTHOR]

This case report presents a 3-year-old female patient initially diagnosed with polycythemia vera (PV) in 2001. The patient exhibited elevated red blood cell (RBC) counts, high hemoglobin (Hb) levels, hyperleukocytosis, and moderate thrombocytosis, with sporadic abdominal pain and significant splenomegaly. Despite various treatments, including phlebotomies, hydroxyurea, and alphainterferon, the patient struggled to maintain optimal hematocrit levels and experienced persistent symptoms. Subsequent genomic analysis revealed a rare JAK2 G301R mutation alongside the canonical JAK2 V617F mutation, potentially contributing to disease severity. In 2023, the patient started Ropeginterferon alfa-2b, leading to improved hematological parameters and symptom relief. The case underscores the challenges in managing PV, particularly in young patients, and highlights the potential clinical significance of additional JAK2 mutations/variants and the potential benefits of Ropeginterferon alfa-2b in achieving better disease control. [ABSTRACT FROM AUTHOR]

Background: It has been discovered that Janus kinase 2 (JAK2) exon12 mutations lead to the polycythemia vera (PV) phenotype, while somatic mutations of calreticulin (CALR) are associated with essential thrombocythemia (ET) or primary myelofibrosis. In this article, we report a case of ET with coexistence of JAK2 exon12 and CALR mutations. The objective of this study was to elucidate the pathogenicity mechanism of a JAK2 exon12 mutation (JAK2N533S) and the role of the coexistence of mutations on the hematological phenotype. Methods: We designed a colony analysis of tumor cells obtained from this patient, and attempted to identify mutant genes using DNA from hair follicles. Mutation impairment prediction and conservative analysis were conducted to predict the mutation impairment and structure of JAK2N533S. In addition, we conducted a functional analysis of JAK2N533S by constructing Ba/F3 cell models. Results: Three distinct tumor subclones, namely JAK2N533Shet+/CALRtype1het+, JAK2N533Shet+/CALRwt, and JAK2N533Shet+/CALRtype1hom+, were identified from the 17 selected erythroid and 21 selected granulocyte colonies. The analysis of hair follicles yielded positive results for JAK2N533S. According to the bioinformatics analysis, JAK2N533S may exert only a minor effect on protein function. Functional studies showed that JAK2N533S did not have a significant effect on the proliferation of Ba/F3 cells in the absence of interleukin-3 (IL-3), similar to wild-type JAK2. Notably, there were no increased phosphorylation levels of JAK2-downstream signaling proteins, including signal transducer and activator of transcription 3 (STAT3) and STAT5, in Ba/F3 cells harboring the JAK2N533S. Conclusion: Our study revealed that the JAK2N533Shet+/CALRtype1het+ subclone was linked to a significant expansion advantage in this patient, indicating that it may contribute to the development of the ET phenotype. We further demonstrated that JAK2N533S, as a noncanonical JAK2 exon12 mutation, is a germline mutation that may not exert an effect on cell proliferation and protein function. These results and the present body of available data imply that certain noncanonical JAK2 mutations are not gain-of-function mutations leading to the development of myeloproliferative neoplasms. [ABSTRACT FROM AUTHOR]

Simple Summary: The human activin receptor type I (ACVR1) is a complex protein that regulates production of hepcidin on hepatocytes and red blood cells. Hepcidin is a small peptide that regulates iron metabolism and plasma iron levels. High hepcidin levels are associated with anemia, which is a hallmark of myelofibrosis. Myelofibrosis is a cancer of the bone marrow, characterized by fibrosis and anemia, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact prognosis in myelofibrosis. Ruxolitinib and fedratinib (JAK inhibitors) may exacerbate anemia in myelofibrosis patients. Momelotinib and pacritinib are potent ACVR1 inhibitors that are preferable to treat cytopenic patients with myelofibrosis. In September 2023, momelotinib was approved as a treatment for anemic patients with myelofibrosis based on the phase 3 clinical trials SIMPLIFY-1 and MOMENTUM, which demonstrated the marked anemia benefits of momelotinib. Other ACVR1 inhibitors (e.g., zilurgisertib) are evaluated in early phase clinical trials as treatments for anemia in MF patients. Activin receptor type I (ACVR1) is a transmembrane kinase receptor belonging to bone morphogenic protein receptors (BMPs). ACVR1 plays an important role in hematopoiesis and anemia via the BMP6/ACVR1/SMAD pathway, which regulates expression of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin levels are inversely associated with plasma iron levels, and chronic hepcidin expression leads to iron-restricted anemia. Anemia is one of the hallmarks of myelofibrosis (MF), a bone marrow (BM) malignancy characterized by BM scarring resulting in impaired hematopoiesis, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact MF prognosis. Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis. In September 2023, momelotinib was approved as a treatment for patients with MF and anemia. Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients. [ABSTRACT FROM AUTHOR]

Transcription factor 3 (TCF3) is a DNA transcription factor that modulates megakaryocyte development. Although abnormal TCF3 expression has been identified in a range of hematological malignancies, to date, it has not been investigated in myelofibrosis (MF). MF is a Philadelphia-negative myeloproliferative neoplasm (MPN) that can arise de novo or progress from essential thrombocythemia [ET] and polycythemia vera [PV] and where dysfunctional megakaryocytes have a role in driving the fibrotic progression. We aimed to examine whether TCF3 is dysregulated in megakaryocytes in MPN, and specifically in MF. We first assessed TCF3 protein expression in megakaryocytes using an immunohistochemical approach analyses and showed that TCF3 was reduced in MF compared with ET and PV. Further, the TCF3-negative megakaryocytes were primarily located near trabecular bone and had the typical "MF-like" morphology as described by the WHO. Genomic analysis of isolated megakaryocytes showed three mutations, all predicted to result in a loss of function, in patients with MF; none were seen in megakaryocytes isolated from ET or PV marrow samples. We then progressed to transcriptomic sequencing of platelets which showed loss of TCF3 in MF. These proteomic, genomic and transcriptomic analyses appear to indicate that TCF3 is downregulated in megakaryocytes in MF. This infers aberrations in megakaryopoiesis occur in this progressive phase of MPN. Further exploration of this pathway could provide insights into TCF3 and the evolution of fibrosis and potentially lead to new preventative therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction: Polycythemia vera (PV) is one of the myeloproliferative neoplasms (MPN) diagnosed by World Health Organization (WHO) criteria 2016, which requires the presence of 3 major criteria: high hemoglobin/hematocrit, bone marrow findings, and Janus Kinase 2 (JAK2) mutation or two major and one minor criteria, including erythropoietin (EPO) level. However, in clinical practice, difficulties in diagnosis can arise as it may be masked by secondary causes for erythrocytosis such as smoking or obstructive sleep apnea (OSA). Case Presentation: Here, we report a 55-year-old gentleman, morbidly obese with OSA on home continuous positive airway pressure (CPAP) machine, who was incidentally found to have polycythemia. Further evaluation confirmed the diagnosis of PV. Conclusion: PV can be masked by the assumption of secondary polycythemia based on history. This underscores the importance of screening such cohort through JAK2 and EPO testing to avoid missing PV. [ABSTRACT FROM AUTHOR]

IntroductionPolycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis and an intrinsic risk of transformation into acute myeloid leukemia (AML), known as blast-phase (BP) disease, a condition typified by dismal prognosis. In PV, the evolution to BP generally occurs through an overt fibrotic progression, represented by the post-PV myelofibrotic (MF) stage. However, direct leukemic transformation from PV may also occur in up to ~50% of patients. In this study, we sought to shed light on the morphological, clinical, and molecular features that may differentiate BP arising from a direct transition from the PV stage (post-PV-BP) from those evolving through a diagnosis of post-PV myelofibrosis (post-PV-MF-BP). Methods and resultsWe retrospectively analyzed a cohort of post-PV-BP (n=5) and post-PV-MF-BP (n=5). We found that BP arising from PV directly displayed significantly lower leukocyte count (median 2.93 × 109/L, range: 2.30–39.40 vs. median 41.05 × 109/L, range: 5.46–58.01; P=0.03), and spleen diameter (14.0 cm, range: 11.5–20.0 vs. 25.5 cm, range: 18–26; P=0.03) as compared to those experiencing an overt fibrotic stage. The most striking differences emerged from bone marrow (BM) morphological analysis: all post-PV-BP were characterized by significantly higher cellularity (median 70%, range: 60%–98% vs. 28%, range: 2%–41%, P=0.0245), lower degree of fibrosis (fibrosis grade 1 vs. fibrosis grade 3 in all cases, P=0.008) and dysplastic features involving all three lineages, most prominently the erythroid and megakaryocytic compartment. Next-generation sequencing (NGS) analysis revealed that post-PV-BP cases were enriched in mutations located in genes involved in DNA methylation such as DNMT3A, IDH1/2, and TET2 (45% vs. 15%, P=0.038). DiscussionWith all the limits of the small number of patients for each cohort, our data suggest that BPs that arise directly from PV present a peculiar phenotype, consistent with the molecular signature of the disease, typified by mutations of genes occurring with a high frequency in Myelodysplastic Syndromes (MDS) and MDS/MPN. Further studies in larger cohorts are warranted to translate these observations into robust evidence that may advise therapeutic choices.

Abstract Background Studies have shown that some single nucleotide polymorphisms (SNPs) could serve as excellent markers in foretelling the treatment outcome of interferon (IFN) in myeloproliferative neoplasms (MPN). However, most work originated from western countries, and data from different ethnic populations have been lacking. Methods To gain insights, targeted sequencing was performed to detect myeloid‐associated mutations and SNPs in eight loci across three genes (IFNL4, IFN‐γ, and inosine triphosphate pyrophosphatase [ITPA]) to explore their predictive roles in our cohort of 21 ropeginterferon alpha‐2b (ROPEG)‐treated MPN patients, among whom real‐time quantitative PCR was also performed periodically to monitor the JAK2V617F allele burden in 19 JAK2V617F‐mutated cases. Results ELN response criteria were adopted to designate patients as good responders if they achieved complete hematological responses (CHR) within 1 year (CHR1) or attained major molecular responses (MMR), which occurred in 70% and 45% of the patients, respectively. IFNL4 and IFN‐γ gene SNPs were infrequent in our population and were thus excluded from further analysis. Two ITPA SNPs rs6051702 A>C and rs1127354 C>A were associated with an inferior CHR1 rate and MMR rate, respectively. The former seemed to be linked to grade 2 or worse hepatotoxicity as well, although the comparison was of borderline significance only (50%, vs. 6.7% in those with common haplotype, p = 0.053). Twelve patients harbored 19 additional somatic mutations in 12 genes, but the trajectory of these mutations varied considerably and was not predictive of any response. Conclusions Overall, this study provided valuable information on the ethnics‐ and genetics‐based algorithm in the treatment of MPN.

Polycythemia vera (PV) is a clonal myeloproliferative disorder that is often associated with neurological symptoms. Rare manifestations of PV may include movement disorders (mainly chorea) and cognitive impairment (CI), which are fully or partially reversible with appropriate treatment. We present a case of chorea with CI in a 69-year-old man with a confirmed с1849G>T (V617F) mutation in the JAK2 gene with no vascular pathology on neuroimaging. In this patient, there is a clear correlation between the regression of the movement disorders with therapeutic phlebotomy and the start of treatment with hydroxyurea, which allows the conclusion that chorea has the secondary form. The cognitive symptoms remained at the same level after the start of treatment and during the one-year follow-up and did not develop further. In view of the patient's age, a concomitant neurodegenerative disease cannot be ruled out. In elderly patients with new-onset chorea and CI, it is therefore important to consider PV as a possible cause of these disorders, as early diagnosis of this condition allows timely initiation of effective treatment and prevention of the development of complications.

Andrea Duminuco,1,2 Patrick Harrington,1 Claire Harrison,1 Natalia Curto-Garcia1 1Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Haematology with BMT Unit, A.O.U. Policlinico “G.Rodolico-San Marco”, Catania, ItalyCorrespondence: Claire Harrison, Guys’ and St Thomas’ Hospital, London, SE1 9RT, UK, Tel +207 188 2742, Email Claire.harrison@gstt.nhs.ukAbstract: Polycythemia vera (PV) is a subtype of myeloproliferative neoplasms characterized by impaired quality of life and severe complications. Despite the increasingly in-depth knowledge of this condition, it necessitates a multifaceted management approach to mitigate symptoms and prevent thrombotic and hemorrhagic events, ensuring prolonged survival. The therapeutic landscape has been revolutionized in recent years, where venesection and hydroxycarbamide associated with antiplatelet therapy have a central role and are now accompanied by other drugs, such as interferon and Janus kinase inhibitors. Ongoing research and advancements in targeted therapies hold promise for further enhancing the therapeutic choice for PV management.Keywords: polycythemia vera, barriers to treatment, current approach, future perspectives

Giulia Benevolo,1 Monia Marchetti,2 Remo Melchio,3 Eloise Beggiato,1 Chiara Sartori,4 Carlo Alberto Biolé,5 Davide Rapezzi,6 Benedetto Bruno,1,7 Alberto Milan8 1University Hematology Division, Città della Salute e della Scienza di Torino, Turin, Italy; 2Hematology and Transplant Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; 3Division of Internal Medicine, A.O. S. Croce E Carle, Cuneo, Italy; 4Cardiology, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; 5SCDO Cardiology, AOU San Luigi Gonzaga Orbassano, Turin, Italy; 6Hematology Division A.O. S. Croce e Carle, Cuneo, Italy; 7Department of Molecular Biotechnolgies and Medical Sciences, University of Turin, Turin, Italy; 8Department of Medical Sciences, University of Turin, Città della Salute e della Scienza di Torino, Turin, ItalyCorrespondence: Giulia Benevolo, University Hematology Division, Città della Salute e della Scienza di Torino, via Genova 3, Turin, 10126, Italy, Tel +39 011 633 4301, Fax +39 011 633 4187, Email gbenevolo@cittadellasalute.to.itAbstract: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory cytokine production. Patients with PV present with a range of thrombotic and hemorrhagic symptoms that affect quality of life and reduce overall survival expectancy. Thrombotic events, transformation into acute myeloid leukemia, and myelofibrosis are largely responsible for the observed mortality. Treatment of PV is thus primarily focused on symptom control and survival extension through the prevention of thrombosis and leukemic transformation. Patients with PV frequently experience thrombotic events and have elevated cardiovascular risk, including hypertension, dyslipidemias, obesity, and smoking, all of which negatively affect survival. To reduce the risk of thrombotic complications, PV therapy should aim to normalize hemoglobin, hematocrit, and leukocytosis and, in addition, identify and modify cardiovascular risk factors. Herein, we review what is currently known about the associated cardiovascular risk and propose strategies for diagnosing and managing patients with PV.Plain Language Summary: Patients with the myeloproliferative neoplasm (MPN) polycythemia vera (PV) are at increased risk of cardiovascular (CV) events, including stroke, heart attacks, and peripheral arterial disease. High blood pressure, smoking, and dyslipidemia are common in MPN and contribute to the increased cardiovascular risk. Effectively controlling cardiovascular risk factors in PV, along with appropriate hematological therapy such as direct-acting oral anticoagulants alone or in combination with aspirin, may improve the outcomes of patients with PV, but further research is needed.Keywords: cardiovascular risk, myeloproliferative neoplasms, polycythemia vera, thrombosis

Splenic infarction is a medical condition characterized by compromised blood flow to the spleen, resulting in partial or complete organ infarction. This condition is commonly observed in patients with an increased risk of thrombosis, such as those with Polycythemia Vera (PV).A 40-year-old female patient presented with fatigue, weakness, and an enlarged spleen, further tests revealed elevated levels of hemoglobin, white blood cells, and platelets. A bone marrow biopsy and positive Jack II mutations confirmed the diagnosis of PV. The patient later developed portal hypertension, varices, and splenic infarction.This case report aims to raise awareness about the potential complications of PV and emphasizes the importance of early intervention to prevent serious consequences such as splenic infarction. Additionally, it highlights the role of splenectomy in managing complications associated with PV.

We present a case of a 59-year-old male diagnosed with polycythemia vera (PV) for many years, who presented with a relatively abrupt onset of heavy constitutional symptoms, including fatigue, night sweats, and a 10% weight loss over 6 weeks. Despite the known initial diagnosis of PV, the presence of profound B-symptoms prompted further investigation. A positron emission tomography/computed tomography (PET/CT) scan with 18F-Fluorodeoxyglucose ([18F]FDG) was performed to exclude malignant diseases. The [18F]FDG PET/CT revealed intense metabolic activity in the bone marrow of the proximal extremities and trunk skeleton, as well as a massively enlarged spleen with increased metabolic activity. Histopathologically, a transformation to myelofibrosis was revealed on a bone marrow biopsy. The case intends to serve as an exemplification for [18F]FDG PET/CT in PV with transformation to myelofibrosis (post-PV myelofibrosis). [ABSTRACT FROM AUTHOR]

We report two patients with chorea associated with polycythaemia vera, in whom the haematocrit and haemoglobin were within the reference range. Polycythaemia vera is potentially easily treatable and so is important to consider in people developing late-onset chorea. [ABSTRACT FROM AUTHOR]

Serum erythropoietin (sEPO) is an initial screening tool for distinguishing polycythemia vera (PV) from secondary erythrocytosis (SE), but defining ‘subnormal’ sEPO levels for PV diagnosis remains contentious, complicating its clinical utility. This study compares the diagnostic performance of sEPO across established subnormal limits, including reference interval (RI), clinical decision limit (CDL), and functional reference limit. sEPO levels were analyzed in 393 healthy donors (HDs) and 90 patients (41 PV and 49 SE), who underwent bone marrow biopsy and genetic tests due to erythrocytosis. The RI (2.5–97.5 percentile from HDs) of sEPO was 5.3–26.3 IU/L. A CDL of 3.1 IU/L, determined by ROC analysis in erythrocytosis patients, had a sensitivity of 80.5% and specificity of 87.8% for diagnosing PV. A functional reference limit of 7.0 IU/L, estimated based on the relationship between sEPO and hemoglobin, hematocrit, and WBC, increased sensitivity to 97.6% but decreased specificity to 46.7%. Using 5.3 IU/L as a ‘subnormal’ limit identified all three JAK2-negative PV cases, increasing the sensitivity and negative predictive value to 97.6% and 97.0%, respectively. Combining the RI, CDL, and functional reference limit may improve PV diagnostic accuracy.

Abstract Background Exercise therapy during cancer treatment reduces symptom burden and improves quality of life (QoL). Polycythemia vera (PV) is a myeloproliferative neoplasia associated with good overall survival (up to decades) but a significant symptom burden, including thromboembolic events and dysesthesias. There are no specific exercise recommendations for patients with PV. Thus, we aimed to determine the exercise preferences of patients with PV and to derive specific recommendations based on the most commonly reported symptoms. Methods This multicenter survey included patients with PV ≥18 years old. Demographic, clinical, and disease burden data were collected. The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1–30 (mild), 31–70 (moderate), or 71–100 (severe). The patients' information needs about physical activity (PA) and exercise preferences were recorded depending on their motivation and analyzed with regard to demographic aspects. Results The sample comprised 182 patients (68% female, 61 ± 12 years). The prevalence of moderate‐to‐severe symptoms was 60% for fatigue, 44% for concentration problems, and 35% for bone/muscle pain. Other commonly reported symptoms included skin reactions (49%), splenomegaly (35%), and increased bleeding tendency (28%). Overall, 67% of respondents requested more information regarding PA. Patients with PV preferred individual training (79%) located outdoors (79%) or at home (56%). Regarding the amount of training, sports‐inactive patients preferred a frequency of 1–2 times/week and session durations of 15–45 min, whereas sports‐active patients preferred 3–4 times/week and 30–60 min (p

Jing Yuan, Xuan Liu, Zhenzhen Wang, Liyuan Li, Fuxu Wang Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaCorrespondence: Fuxu Wang, Department of Hematology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email cinderella8886@163.comAbstract: Concurrent polycythemia vera with newly diagnosed multiple myeloma is extremely rare. We described a 70-year-old woman with concurrent polycythemia vera and newly diagnosed multiple myeloma. Genetic testing confirmed the JAK2 V617F mutation for the first time, while determination of serum erythropoietin decreased. A retrospective review of our patient’s case was conducted thereafter, and related literature was systemically reviewed. We totally identified eight cases with concurrent polycythemia vera with newly diagnosed multiple myeloma, which were further analyzed and compared. The present case is the first patient of newly diagnosed multiple myeloma with diagnosis of polycythemia vera confirmed by positive JAK2 V617F mutation. Abnormal erythremia, hepatosplenomegaly and thrombosis history suggested comorbidity of polycythemia vera with newly diagnosed multiple myeloma. The bortezomib-based chemotherapy regimen seemed to be effective on controlling the proliferation of erythrocyte. Whereas the pathogenesis of these two entities remains to be further investigated.Keywords: polycythemia vera, newly diagnosed multiple myeloma, concurrence, JAK2 V617F

Abstract Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%–20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and ‐in primary MF‐ also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p‐y). This rate reached respectively 4.3% and 4.5% p‐y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p‐y and it reached 4.86% p‐y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion‐dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p‐y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.

Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome–positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is the key genetic event of CML, whereas JAK2/MPL/CALR mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of BCR::ABL1 and JAK2 has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or JAK2 aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, BCR::ABL1 translocation occurs in patients with a history of JAK2-positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient’s treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of BCR::ABL1 and JAK2 co-occurrence. The interaction between JAK2 and BCR::ABL1 clones during the disease course as well as therapy and outcome are presented.

This case report presents a 3-year-old female patient initially diagnosed with polycythemia vera (PV) in 2001. The patient exhibited elevated red blood cell (RBC) counts, high hemoglobin (Hb) levels, hyperleukocytosis, and moderate thrombocytosis, with sporadic abdominal pain and significant splenomegaly. Despite various treatments, including phlebotomies, hydroxyurea, and alpha-interferon, the patient struggled to maintain optimal hematocrit levels and experienced persistent symptoms. Subsequent genomic analysis revealed a rare JAK2 G301R mutation alongside the canonical JAK2 V617F mutation, potentially contributing to disease severity. In 2023, the patient started Ropeginterferon alfa-2b, leading to improved hematological parameters and symptom relief. The case underscores the challenges in managing PV, particularly in young patients, and highlights the potential clinical significance of additional JAK2 mutations/variants and the potential benefits of Ropeginterferon alfa-2b in achieving better disease control.

We applied a parametric Markov five-state model, on a well-characterized international cohort of 1,545 patients with polycythemia vera (PV; median age 61 years; females 51%), in order to examine the impact of incident thrombosis on the trajectory of death or disease progression. At a median follow-up of 6.9 years, 347 (23%) deaths, 50 (3%) blast phase (BP), and 138 (9%) fibrotic (post-PV MF) transformations were recorded. Incident thrombosis occurred at a rate of 2.62% pt/yr (arterial 1.59% and venous 1.05%). The probability of death, in the first 10 years, for 280 (18%) patients who developed thrombosis during follow-up was 40%, which was two-fold higher than that seen in the absence of thrombosis or any other transition state (20%; p < 0.01); the adverse impact from thrombosis was more apparent for arterial (HR 1.74; p < 0.01) vs venous thrombosis (p=NS) and was independent of other fixed (i.e., age, prior venous thrombosis, leukocytosis) or time-dependent (i.e., progression to BP or MF) risk variables. The transition probability to post-PV MF increased over time, in a linear fashion, with a rate of 5% capped at 5 and 10 years, in patients with or without incident thrombosis, respectively. The impact of thrombosis on transition probability to death or post-PV MF tapered off beyond 10 years and appeared to reverse direction of impact on MF evolution at the 12-year time point. These observations suggest thrombosis in PV to be a marker of aggressive disease biology or a disease-associated inflammatory state that is consequential to both thrombosis and disease progression. [ABSTRACT FROM AUTHOR]

Background: Polycythemia vera (PV), characterized by elevated red blood cell counts, poses challenges to cardiovascular health with potential impacts on cardiac function. Myocardial infarction (MI) and heart failure are major causes of mortality in PV patients. Early detection of left ventricular systolic dysfunction is crucial for optimizing outcomes. Methods: Fifty‐two PV patients and 45 healthy controls were recruited. Four‐dimensional speckle tracking echocardiography (4D‐STE) and fragmented QRS complexes (fQRS) on electrocardiograms were utilized to assess cardiac mechanics. Hematological and echocardiographic parameters were measured, and statistical analyses were performed. Results: PV patients exhibited significantly higher hematocrit and red cell distribution width compared to controls. Global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS) were lower in PV patients. fQRS complexes were associated with longer disease duration and reduced GCS and GAS values. Hematocrit correlated positively with LV‐GCS and LV‐GAS. Multiple linear regression revealed that disease duration and fQRS presence independently predicted LV‐GAS. Conclusion: This study underscores the intricate link between elevated red blood cell counts, disease duration, and cardiac function in PV patients. Combining 4D‐STE and fQRS complexes enhances the identification of early left ventricular systolic dysfunction. These findings offer potential improvements in recognizing and managing cardiovascular complications in PV patients, with implications for future research and clinical practice. Further investigations are needed to elucidate underlying mechanisms and validate these markers in larger cohorts. [ABSTRACT FROM AUTHOR]

Introduction: The role of inflammation in the pathophysiology of polycythemia vera (PV) is important. The presence of JAK2 mutations is important in the diagnosis of PV, and serum levels of erythropoietin (EPO) also play a supporting role. However, serum EPO levels show some limitations. The neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) are a readily available marker of inflammation. Thus, we examined whether NLR & PLR might diagnose PV in erythrocytosis patients. We compared NLR & PLR and EPO diagnostic values. Methods: We retrospectively reviewed clinical and laboratory data from two referral hospitals. Two hundred and eighty‐five patients with erythrocytosis who underwent a test for the JAK2 mutation were included. It wac classified as the PV group and the secondary polycythemia (SP) group. Results: The median NLR & PLR in the PV group (n = 70) was significantly higher than that in the SP group (n = 170) (NLR: 6.04 vs. 1.77, PLR: 283.18 vs. 101.56, respectively, p < 0.001). In the receiver operating characteristic analysis, the area under the curve of NLR & PLR was significantly higher than that of serum EPO (NLR vs EPO: 0.921 vs. 0.827, p = 0.003; PLR vs EPO: 0.917 vs 0.827, p = 0.003). Conclusion: In conclusion, NLR & PLR were higher in PV than in SP and showed better diagnostic value than serum EPO level, highlighting their potential as minor diagnostic criteria in patients with PV. [ABSTRACT FROM AUTHOR]

The rapid pace of drug development in hematology has led to multiple approvals for myelofibrosis (MF) and polycythemia vera (PV) in recent years. Moreover, there are many innovative agents and combinations being explored for myeloproliferative neoplasms (MPNs). In the past year, there have been several advances in MF, PV, and essential thrombocythemia. In MF, investigational approaches are focusing on strategies to optimize inhibition of signal transduction (including JAK inhibition), modify epigenetics, enhance apoptosis, target DNA replication, transform host immunity, and/or alter the tumor microenvironment. In PV, ropeginterferon alfa‐2b has been introduced to the market in the United States, and data continue to accumulate to support the safety and efficacy of this treatment. Hepcidin mimesis is also emerging as a novel way to treat erythrocytosis. In essential thrombocythemia, ropeginterferon alfa‐2b is being evaluated, as are therapies to modify epigenetics and inhibit CALR. The enhanced focus on MPNs brings hope that our field can improve morbidity and mortality in this group of diseases. Using a variety of mechanisms, many innovative agents and combinations are being explored for myeloproliferative neoplasms. There is great optimism that at least some of the strategies under investigation will bring improved outcomes to patients with these diseases. [ABSTRACT FROM AUTHOR]

Ruxolitinib (RUX) is a potent drug that has been approved by the Food and Drug Administration for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. This study describes the formation of colored charge-transfer complexes (CTCs) of RUX, an electron donor, with chloranilic acid (CLA) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the π-electron acceptors. The CTCs were characterized using UV-visible spectrophotometry. The formation of CTCs in methanol was confirmed via formation of new absorption bands with maximum absorption at 530 and 470 nm for CTCs with CLA and DDQ, respectively. The molar absorptivity and other physicochemical and electronic properties of CTCs were determined. The molar ratio was found to be 1:1 for both CTCs with CLA and CTCs with DDQ. The site of interaction on RUX molecules was assigned and the mechanisms of the reactions were postulated. The reactions were employed as basis for the development of a novel green and one-step microwell spectrophotometric method (MW-SPM) for high-throughput quantitation of RUX. Reactions of RUX with CLA and DDQ were carried out in 96-well transparent plates, and the absorbances of the colored CTCs were measured by an absorbance microplate reader. The MW-SPM was validated according to the ICH guidelines. The limits of quantitation were 7.5 and 12.6 µg/mL for the methods involving reactions with CLA and DDQ, respectively. The method was applied with great reliability to the quantitation of RUX content in Jakavi® tablets and Opzelura® cream. The greenness of the MW-SPM was assessed by three different metric tools, and the results proved that the method fulfills the requirements of green analytical approaches. In addition, the one-step reactions and simultaneous handling of a large number of samples with micro-volumes using the proposed method enables the high-throughput analysis. In conclusion, this study describes the first MW-SPM, a valuable analytical tool for the quality control of pharmaceutical formulations of RUX. [ABSTRACT FROM AUTHOR]