RARE DISEASE
Polycythemia vera
Polycythemia vera
Polycythemia vera
Synonyms: Acquired primary erythrocytosis, Osler-Vaquez disease, PV, Polycythemia rubra vera, Vaquez disease
Synonyms: Acquired primary erythrocytosis, Osler-Vaquez disease, PV, Polycythemia rubra vera, Vaquez disease
Synonyms: Acquired primary erythrocytosis, Osler-Vaquez disease, PV, Polycythemia rubra vera, Vaquez disease
Drug discovery
23
drugs
With orphan designations
Overview
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by somatic JAK2 mutations (>95% of cases), erythrocytosis, and thrombotic risk due to blood hyperviscosity [1][2][6]. Diagnosis requires elevated hemoglobin/hematocrit, JAK2 mutation, and bone marrow panmyelosis per WHO criteria [2][5]. Management focuses on thrombosis prevention through hematocrit control (<45% via phlebotomy), low-dose aspirin, and cytoreductive therapy for high-risk patients [8][13][18].
Burden
Thrombosis: 26% 20-year risk of arterial/venous events (e.g., stroke, pulmonary embolism) [5][12].
Symptoms: Fatigue (50–80%), pruritus (40–60%), splenomegaly (35–50%), and erythromelalgia impair quality of life [4][9][16].
Progression: 10–15% develop post-PV myelofibrosis; 3–5% transform to acute leukemia [2][5][12].
Therapies
First-line: Phlebotomy + aspirin; hydroxyurea or peginterferon for high-risk patients (age >60 or thrombosis history) [5][8][13].
Second-line: Ruxolitinib (JAK inhibitor) for hydroxyurea-resistant/intolerant cases; ropeginterferon alfa-2b for durable responses [3][18][19].
Emerging therapies: Rusfertide (hepcidin mimetic) reduces phlebotomy dependence in clinical trials [3][14].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,824 drug discovery papers about Polycythemia vera, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,824 drug discovery papers about Polycythemia vera, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-11 | First Philippine report of myeloproliferative neoplasms with concurrent JAK2 and BCR::ABL1 mutations.
Myeloproliferative neoplasms (MPNs) are broadly classified into BCR::ABL1-positive chronic myeloid leukaemia (CML) and BCR::ABL1-negative subtypes such as polycythaemia vera (PV), essential thrombocythaemia and primary myelofibrosis. Although traditionally considered mutually exclusive, rare cases of coexisting BCR::ABL1 rearrangement and Janus kinase 2 (JAK2) mutation have increasingly been recognised.We report the first Philippine case series of three patients with concurrent CML and JAK2-positive MPNs. Two patients developed PV 6-9 years after the initial diagnosis of CML despite ongoing tyrosine kinase inhibitor (TKI) therapy and molecular response, while a third patient had persistent thrombocytosis and was later found to have a concomitant JAK2-mutated MPN with fibrotic marrow features after 4 years.Compared with previously reported cases, our series demonstrates similarly delayed emergence of JAK2-mutated clones while highlighting real-world challenges in TKI intolerance, sequential TKI use and the need for combined cytoreductive strategies in a resource-limited setting.
2026-08-09 | The thrombopoietin receptor in myeloproliferative neoplasms: A unifying mechanism of disease pathogenesis and therapeutic targeting.
The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis, are clonal hematopoietic stem cell disorders unified by constitutive thrombopoietin receptor (MPL) signaling. All 3 MPN driver mutations, JAK2, CALR, and MPL, converge on enhanced MPL signaling, establishing the thrombopoietin (TPO)/MPL axis as the central molecular hub linking clonal hematopoiesis to the cardinal manifestations of MPN, including thrombosis, hemorrhage, and fibrotic progression. As the principal regulator of hematopoietic stem cell maintenance and megakaryopoiesis and a key mediator of platelet priming, the TPO/MPL axis links stem cell biology to thromboinflammation and disease progression. This review summarizes the physiologic functions of the TPO/MPL axis, its dysregulation in MPN, and the downstream mechanisms linking aberrant MPL signaling to thrombosis, hemorrhage, and fibrotic progression. We further highlight recent advances in our understanding of TPO/MPL signaling in platelet biology, including its roles in platelet activation, metabolism, and thromboinflammation, and discuss emerging therapeutic strategies targeting the TPO/MPL pathway with the goal of simultaneously reducing thrombohemorrhagic complications, limiting fibrotic progression, and diminishing the malignant stem cell clone.
2026-08-08 | Case Report: Polycythemia vera presenting as persistent unexplained low-grade fever.
Persistent fever as an initial manifestation of polycythemia vera (PV) is uncommon and may lead to diagnostic delay. We report a 72-year-old woman with recurrent low-grade fever for 1 month, with a maximum temperature not exceeding 38.0 °C. Although this presentation did not meet the classic fever-of-unknown-origin temperature threshold, it prompted an FUO-like diagnostic evaluation because routine infectious and autoimmune investigations were unrevealing and empirical antimicrobial therapy was ineffective. Laboratory evaluation revealed elevated hemoglobin and hematocrit levels, accompanied by leukocytosis and initially high-normal platelet counts that later progressed to thrombocytosis. Chest CT/PET-CT showed diffuse ground-glass/interstitial pulmonary changes; active bacterial pneumonia was considered unlikely based on the absence of respiratory symptoms, procalcitonin at the upper limit of the normal range, negative cultures and sputum smears, and absence of FDG-avid pulmonary consolidation, although a concomitant viral or noninfectious inflammatory pulmonary process could not be completely excluded. Bone marrow biopsy showed hypercellular marrow with panmyelosis and megakaryocytic proliferation, and molecular testing identified a JAK2 V617F mutation with a high allele burden. The diagnosis of PV was established based on the 5th edition of the World Health Organization (WHO) diagnostic criteria. The patient was treated with hydroxyurea and aspirin, resulting in gradual resolution of fever and improvement in hematological parameters. This case highlights that PV should be considered in the differential diagnosis of persistent unexplained low-grade fever when erythrocytosis and other myeloproliferative features are present, while alternative pulmonary causes should be assessed carefully.
2026-08-04 | Acute erythroid leukaemia transformation in polycythaemia vera with leukemic involvement in liver and ascites.
Polycythaemia vera (PV) may rarely evolve into acute erythroid leukaemia (AEL). We herein report a known case of JAK2 p. V617F mutated PV presenting with progressive hepatosplenomegaly, abdominothoracic lymphadenopathy, ascites and various haematological derangements. Rapid diagnostic work-up revealed extensive marrow, hepatic and ascitic fluid infiltration by many CD71+, LMO2+ and p53+ proerythroblasts. Next generation sequencing showed TP53, ASXL1 and TET2 gene mutations. A chemotherapeutic regimen of ruxolitinib, azacitidine and venetoclax was initiated. A comprehensive review of the English literature emphasises clinical, morphologic, immunophenotypic and genetic characteristics of AEL transformation in PV.
2026-08-03 | [Disappearance of del (7q) with lenalidomide in myelofibrosis complicated with multiple myeloma].
Lenalidomide, an immune-modulatory drug, is used to treat multiple myeloma (MM). Lenalidomide has also been investigated as a treatment for myelofibrosis (MF); however, its efficacy in this setting has not been established. We report a case of secondary MF progressing from polycythemia vera (PV) that had the poor prognostic factor del (7q) and concurrent MM, in which del (7q) disappeared and MF improved after treatment with lenalidomide. A 69-year-old woman presented to our hospital with PV in March 2022. Bone marrow examination revealed grade 2 fibrosis. The diagnosis was secondary MF progressing from PV, with JAK2 V617F and del (7q), along with IgG-κ monoclonal gammopathy of undetermined significance (MGUS). In May 2023, the appearance of new bone lesions indicated progression of MGUS to MM. Treatment with lenalidomide plus dexamethasone achieved a partial response. After this treatment, del (7q) disappeared and MF improved. The efficacy of lenalidomide in MF with del (7q) has never been reported. This case shows that lenalidomide may improve the prognosis of MF with del (7q).
cell therapies
2026-07-30 | Evaluation of the efficacy of erythrocytapheresis and phlebotomy in the treatment of polycythemia.
Systematic comparison of the efficacy and safety of erythrocytapheresis and phlebotomy. A retrospective analysis of 108 polycythemia patients categorized into four treatment groups: 1, 2, or 3 sessions of phlebotomy, and 1 session of erythrocytapheresis. The primary outcome was HGB change. One-way analysis of variance (ANOVA), Kruskal-Wallis H test, t-tests, and linear regression were used to compare efficacies and identify predictive factors, with subgroup analyses for polycythemia vera (PV) and high-altitude polycythemia (HAPC). Linear trend analysis was performed to evaluate the dose-response relationship.The references cited in this article were retrieved through the PUBMED database. A significant difference in HGB change was observed among four groups. 3 sessions of phlebotomy were superior to 1 and 2 sessions. 1 session of erythrocytapheresis achieved comparable HGB change to 2-3 phlebotomy sessions. Linear trend analysis confirmed HGB change increased with phlebotomy sessions. In the PV subgroup, baseline HGB and female gender were predictors of HGB change. In the HAPC subgroup, only baseline HGB was a significant predictor. 2-3 sessions of phlebotomy are non-inferior to 1 session of erythrocytapheresis in efficacy, with higher safety and cost-effectiveness, and baseline HGB is a universal predictor of therapeutic efficacy.
2025-05-28 | CRISPR/Cas9-Based Modeling of JAK2 V617F Mutation in K562 Cells Reveals Enhanced Proliferation and Sensitivity to Therapeutic Agents.
The Janus kinase 2 (JAK2) protein fulfills an important role in hematopoiesis via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, as it provides the genetic driver of BCR::ABL1-negative myeloproliferative neoplasms (MPNs), which are clinically manifested as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The most common cause of MPNs is the mutation of JAK2 V617F in the JAK2 gene, which results in increased cell proliferation. However, both the pathogenesis and treatment regimen of BCR::ABL1-negative MPNs remain poorly understood. The aim of the present study was to establish K562 cell lines with a point mutation in exon 14 (JAK2p.V617F) using CRISPR/Cas9 technology. The modified JAK2 V617F cell lines were examined for the gene mutation using droplet digital PCR (DDPCR), and the presence of the mutation was confirmed by DNA sequencing. Modified cells were characterized by measuring JAK2 gene expression and the extent of cell proliferation. Interferon α2a (IFN-α2a) and arsenic trioxide were also administered to the cells to explore their potential effects. The JAK2 V617F-mutated cells were found to exhibit a higher level of JAK2 gene expression compared with the wild type. Interestingly, a significant increase in the proliferation rate was observed with the modified cells compared with the wild type cells (p < 0.001), as assessed from the JAK2 gene expression levels. Furthermore, the treatments with IFN-α2a and arsenic trioxide led to the preferential suppression of the cell proliferation rate of the K562 expressing mutant JAK2 cells compared with the wild type cells, and this suppression occurred in a dose-dependent manner(p < 0.01). Moreover, the modified cells were able to differentiate into megakaryocyte-like cells following stimulation with phorbol 12 myristate 13 acetate (PMA). Taken together, the results of the present study have shown that the CRISPR/Cas9-modified JAK2 V617F model may be used as a disease model in the search of novel therapies for MPNs.
2025-05-24 | Clinical application of erythrocytapheresis in the treatment of erythrocytosis.
This study aimed to clarify the clinical utility of erythrocytapheresis as a treatment for erythrocytosis, including polycythemia vera and secondary erythrocytosis. A retrospective analysis was conducted on 83 patients (84.34 % male, mean age 49.66 years (16.23 years)) who underwent a total of 104 erythrocytapheresis sessions between September 2021 and April 2025. The key parameters measured included the depleted red blood cell (RBC) volume, the hemoglobin (HB) and hematocrit (Hct) reductions, and adverse reactions. Erythrocytapheresis significantly reduced the post-treatment RBC counts (25.22 %), the HB (25.19 %) level and the Hct (23.62 %), the white blood cell counts, (23.37 %) and the platelet counts (8.38 %) (all p < 0.05). The median depleted RBC volume was 1405.5 mL (range 1011.75-1677.5 mL). The median post-treatment target Hct was 40 % (range 40-45 %). The mean post-treatment Hct was in fact 47.57 % (6.54 %), which was higher than the target, and the mean Hct error ratio was 14.23 % (12.95 %). When the replacement solution was physiological saline, an adverse reaction (hypotension) occurred during 4.81 % of the 104 erythrocytapheresis sessions, but only in patients with a depleted RBC volume/weight (D/W) ≥ 25 mL/kg. No significant differences were observed between the Spectra Optia and COM.TEC blood cell separators. Erythrocytapheresis effectively reduces the RBC mass in patients with erythrocytosis.In rough terms, the post-treatment target Hct = the post-treatment Hct × 0.88, our research team has officially designated this formula as the 'Southwest Formula'. In the future, we will continue to expand the sample size to enhance the precision of this formula and better guide the clinical application of erythrocytapheresis.
2024-08-31 | Impact of Phlebotomy on Quality of Life in Low-Risk Polycythemia Vera.
Polycythemia vera is an indolent myeloproliferative disorder that predisposes patients to venous and arterial thrombosis and can transform into myelofibrosis and acute myeloid leukemia. Consistent phlebotomy prevents life-threatening cerebrovascular and coronary artery disease and prolongs survival in low-risk polycythemia vera (patients under 60 years without thrombosis). However, despite its effectiveness in preventing serious complications, phlebotomy does not necessarily enhance the quality of life (QoL). This review assesses QoL issues associated with low-risk PV, explores alternative management strategies such as erythrocytapheresis, and discusses the roles of hydroxyurea, peginterferon, ruxolitinib, and other novel agents in potentially improving disease management and patient outcomes.
2024-06-17 | A comparison between erythrocytapheresis and venesection for the treatment of JAK2-mutated polycythaemia.
JAK2-mutated polycythaemia vera (PV) is associated with reduced survival because of thrombotic events and haematological disease transformation. Therapeutic venesection has traditionally been used to lower haematocrit, but the technique of erythrocytapheresis has emerged over the last decade. To compare erythrocytapheresis with venesection as treatment for PV by assessing medical efficacy and financial viability. One hundred sixteen patients with PV who received red cell depletion therapy at Barwon Health between 2014 and 2021 were identified. The haematocrit drop after each session, interval between treatment times and number of sessions required to achieve a haematocrit <0.45 were compared with an independent t test. Thrombosis rates were compared with Pearson's chi-squared test. Cost-funding analysis was done by assessing the Weighted Inlier Equivalent Separation and National Weighted Activity Unit funding models. Patients treated with erythrocytapheresis achieved a greater haematocrit drop each treatment session (0.075 vs 0.03, P < 0.01), required fewer sessions to achieve a haematocrit <0.45 (1 vs 4, P < 0.01) and experienced fewer thrombotic complications (8.7% vs 32.1%, P = 0.02) than those treated with venesection. Cost-funding analysis demonstrated that erythrocytapheresis was more financially viable with a surplus of AU$297 per session compared to a deficit of AU$176 with venesection. Even if funding for venesection is increased, the cost of erythrocytapheresis may be mitigated by a lower number of procedures required per year (3.8 vs 5.3, P < 0.01). Erythrocytapheresis is more efficacious than venesection for the treatment of PV and is accompanied by rapid reductions in haematocrit and reduced thrombotic complications.
proteins
2026-08-07 | Ropeginterferon alfa-2b in Polycythemia Vera: A systematic review and meta-analysis.
Ropeginterferon alfa-2b, a novel monopegylated interferon with improved pharmacokinetics, has emerged as a promising cytoreductive agent for managing polycythemia vera (PV). Despite increasing adoption, evidence synthesis of its efficacy and safety compared to standard care remains limited. The manuscript aimed to evaluate the efficacy of ropeginterferon alfa-2b in comparison to standard treatment options, including hydroxyurea and phlebotomy, in achieving complete hematologic response, partial molecular response (PMR), and reducing JAK2V617F allele burden in patients with PV. A systematic search of 4 databases was conducted up to April 2025, following PRISMA 2020 guidelines. Randomized controlled trials (RCTs) comparing ropeginterferon alfa-2b with standard therapies in PV patients were included. Meta-analyses were performed using random-effects models to derive odds ratios for dichotomous outcomes and mean differences (MDs) for continuous outcomes. Sensitivity and subgroup analyses were conducted, and risk of bias was assessed using RoB 2.0. Three RCTs comprising 522 patients were analyzed. Ropeginterferon alfa-2b showed no statistically significant advantage overall or over hydroxyurea for complete hematological response (CHR), PMR, or JAK2 allele burden reduction. However, subgroup analyses revealed significant benefits over phlebotomy alone in all 3 outcomes: CHR (odds ratio [OR] 3.05; 95% confidence interval [CI]: 1.36-6.80; P = .007), PMR (OR 36.34; 95% CI: 2.11-625.93; P = .01), and allele burden reduction (MD -13.70; 95% CI: -19.24 to -8.16; P < .00001). Ropeginterferon alfa-2b demonstrates no statistically significant difference compared to hydroxyurea, but gives better outcomes over phlebotomy in short-term efficacy for PV management. Its favorable molecular and hematologic outcomes support its role as a disease-modifying therapy, particularly in low-risk patients. However, larger and longer-term trials are needed to confirm these benefits across broader populations.
2026-07-16 | Successful Topical Treatment of Hydroxyurea-Induced Ulcers Without Drug Discontinuation: A Case Report.
Hydroxyurea, an antineoplastic agent, is widely used to treat essential thrombocythemia and polycythemia vera. Although hydroxyurea-induced skin ulcers are uncommon, they are a recognized long-term adverse effect. Current management generally recommends discontinuation of hydroxyurea as the mainstay of treatment; however, drug withdrawal may aggravate the underlying hematologic disease. We report a case of bilateral medial malleolar ulcers associated with hydroxyurea therapy in a 65-year-old man with essential thrombocythemia, who showed marked improvement after two months of topical treatment with recombinant bovine basic fibroblast growth factor (rb-bFGF) gel, without discontinuation of hydroxyurea. Complete healing was confirmed at 25-month follow-up, while hematologic disease control was maintained. This case suggests that localized wound care with topical rb-bFGF may represent a feasible therapeutic option in selected patients when hydroxyurea discontinuation is not feasible.
2026-05-03 | Hematologic and molecular response to ropeginterferon alfa-2b in patients with polycythemia vera: a systematic review and meta-analysis.
Ropeginterferon alfa-2b is an interferon used in the treatment of myeloproliferative neoplasms, particularly polycythemia vera. Its efficacy in achieving hematologic and molecular responses has been demonstrated in clinical trials, but pooled data on long-term outcomes and sustained response remain limited. This systematic review and meta-analysis aimed to evaluate the hematologic and molecular response over 36 months. PubMed, Scopus, Science Direct, and Google Scholar databases were searched to identify studies reporting hematologic and molecular responses to ropeginterferon alfa-2b. Studies were included if they provided data on complete hematologic response (CHR) and JAK2V617F variant allele frequency (VAF) reduction. Pooled proportions and mean reductions were calculated using random-effects models. The pooled proportion of CHR increased progressively from 0.19 (95% CI: 0.04-0.57) at 3 months to 0.73 (95% CI: 0.17-0.97) at 36 months. Molecular response, measured by VAF reduction, deepened over time from - 7.33 (95% CI: -9.85 to -4.81) at 3 months to -54.90 (95% CI: -65.61 to -43.99) at 36 months. Subgroup analyses revealed significant variability in response rates, particularly in early follow-up periods. Ropeginterferon alfa-2b achieves significant and sustained hematologic and molecular responses over 36 months. This makes it a promising treatment for polycythemia vera. While variability in early responses needs further investigation, the sustained long-term efficacy compared to hydroxyurea supports its use in clinical practice. Future studies should focus on identifying predictors of response and optimizing treatment protocols to maximize patient outcomes.
2026-04-11 | Ropeginterferon dose-escalation strategies in polycythemia vera: a systematic review and meta-analysis
Abstract Background Ropeginterferon alfa-2b is increasingly used as a long-acting interferon therapy for polycythemia vera (PV), providing hematologic and molecular benefits. However, clinical studies have implemented different dose-escalation strategies, and their impact on outcomes has not been systematically evaluated. Methods A systematic search of PubMed, Embase, and the Cochrane Library (September 24, 2025) identified studies reporting clinical outcomes of ropeginterferon in PV. Nine studies met eligibility criteria. Two reviewers independently extracted data, and meta-analyses were conducted using random-effects models. Subgroup analyses compared slow dose-up (SDU) and rapid dose-up (RDU) regimens at 1-, 2-, and 3-year follow-up when available. Results The pooled 1-year complete hematologic response (CHR) rate was 0.59 (95% CI, 0.47–0.71). RDU regimens yielded significantly higher CHR than SDU at both 1 year (0.67 vs. 0.41; p < 0.001) and 2 years (0.75 vs. 0.63; p = 0.038). Molecular response (MR) also favored RDU at 1 year (0.59 vs. 0.36; p < 0.001), with differences diminishing at 2 years. The pooled 1-year reduction in JAK2 V617F allele burden was − 22.2% (95% CI, − 34.2% to − 10.2%; p < 0.001). Safety outcomes were favorable, with low rates of thrombosis (4%), serious adverse events (5%), and treatment discontinuation (7%). Conclusions Ropeginterferon alfa-2b provides meaningful hematologic and molecular responses with an acceptable safety profile in PV. Rapid dose-escalation facilitates earlier CHR and MR without increasing toxicity, suggesting titration speed as an important determinant of early treatment optimization.
2026-04-09 | A paradigm shift in the treatment of patients with polycythemia vera. The initial early use of recombinant interferon-alpha.
During the past 35 years, single-arm studies documented the efficacy and safety of recombinant interferon alpha (rIFNα) for treating polycythemia vera (PV). In some patients, 2-5 years of disease-modifying treatment resulted in symptom relief, regression of splenomegaly, normalization of abnormal blood counts and marrow morphology, and sustained JAK2V617F molecular remission. The PROUD-CONTI study showed the superiority of rIFNα compared to hydroxyurea (HU), which led to the European Medicines Agency approval in 2019 of ropeginterferon alpha-2b ("ropegIFN") for ELN-defined high-risk PV patients. In 2021, the Food and Drug Administration (USA) gave unrestricted approval, except for pregnant PV patients. The Low-PV randomized trial established the superiority of ropegIFN compared to phlebotomy-only (PHLEB-O) in ELN-defined low-risk patients. Nevertheless, worldwide, HU remains the cytoreductive drug most often used; maintenance PHLEB-O is still endorsed as maintenance therapy by some hematologists. The National Comprehensive Cancer Network (NCCN, USA) approved ropegIFN as a II-A recommendation for ELN-defined low and high-risk disease; the ELN suggested criteria for using rIFNα in low-risk patients if certain issues developed after PHLEB-O, including more symptoms, progressive splenomegaly, significant leukocytosis, thrombocytosis, or inadequate hematocrit control. These issues are important because even low-risk patients are at increased thrombotic risk, estimated at 2 to 3 times that of the general population. Moreover, as PV progresses, the development of myelofibrosis is the leading cause of morbidity, perhaps abetted by PHLEB-O. Here, we review recent progress in the treatment of PV with rIFNα and discuss our rationales and perspectives for, and the endorsement of the initial treatment with rIFNα of both low and high-risk PV patients, unless a contraindication exists to its use.
antibodies
2026-04-29 | A Phase 1 Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study of DISC-3405, a Novel Recombinant Humanized Monoclonal Antibody Targeting TMPRSS6, in Adult Healthy Volunteers.
Hepcidin is the central regulator of iron homeostasis, controlling iron sequestration and dietary iron absorption. Transmembrane serine protease 6 (TMPRSS6) suppresses hepcidin via the bone morphogenetic protein/small mothers against decapentaplegic (BMP/SMAD) pathway by cleaving the co-receptor hemojuvelin. DISC-3405 is a novel humanized monoclonal antibody that enhances hepcidin expression by inhibiting TMPRSS6, thereby promoting iron restriction. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of DISC-3405 or placebo in 56 healthy participants. DISC-3405 (37.5 to 300 mg) or placebo was administered subcutaneously (SC) or intravenously (IV). DISC-3405 was well tolerated. No deaths, serious adverse events, or participant discontinuations occurred. Most treatment-emergent adverse events were Grade 1 (mild) in severity, with 2 participants reporting Grade 2 (moderate) events following single dosing and no Grade 3/4 (severe/life-threatening) events reported. Median time to maximum plasma concentration was ≈96 to 168 h. Elimination half-life rose from 130 h at 37.5 mg to 265 h at 300 mg, with a clinically relevant half-life of ≈11 days. Absolute bioavailability was 39.7% (75 mg SC vs. IV). Minor accumulation occurred with repeat 4-week dosing of two doses, and PK was greater than dose proportional. DISC-3405 increased hepcidin-25 and reduced serum iron and transferrin saturation across dose levels. Single and repeated dosing of DISC-3405 produced reductions in reticulocyte hemoglobin, hemoglobin, and hematocrit. Overall, DISC-3405 was well tolerated with PK/PD data supporting further development for patients who could benefit from iron restriction, such as those with polycythemia vera.
2025-11-30 | Mesenchymal stromal cells secretory pattern contributes to oncoinflammatory bone marrow microenvironment in polycythemia vera.
Polycythemia vera is a myeloproliferative neoplasm marked by an increased proliferation of erythroid mature and precursors cells in bone marrow and peripheral blood. The pathophysiology is linked to the presence of the JAK2 driver mutation, epigenetic deregulation, and alterations in the bone marrow hematopoietic niche. Multipotent mesenchymal stromal cells (MSC) in the bone marrow, which are crucial for maintenance and development of hematopoietic stem cells, play a role in the communication between neoplastic cells and resident bone marrow cells by releasing various mediators that either suppress or promote tumor progression. These mediators include several essential immunomodulatory molecules, pro-angiogenic and growth factors. We hypothesized that MSC from polycythemia vera patients (Patient Group) would exhibit distinct properties compared to those from healthy donors (Control Group), thereby influencing the hematopoietic niche and contributing to disease pathogenesis. This study characterized MSC from patients, focusing on their secretory, proteomic, and phenotypic properties. MSC from the Patient and Control Groups had similar immunophenotypes and multipotentiality. However, MSC from the Patient Group exhibited reduced immunomodulatory properties, and released distinct soluble immune and angiogenic mediators when compared with the Control Group. Global proteomic analysis revealed that MSC from patients presented upregulated expressions of FAM175B, VP526A, CTTN, MAP4, BAX, and TPD52L2 but a downregulated TNC expression. These results indicate that MSC contribute to the inflammation pattern in the hematopoietic niche. The secretory and proteomic profile of MSC from patients, indicate that these cells may influence immune cell function, induce neoangiogenesis, and alter cell-to-cell interactions within the bone marrow, thereby fostering a pro-tumor microenvironment and favoring disease pathogenesis. These findings highlight the potential of targeting MSC-mediated pathways as a therapeutic strategy in polycythemia vera.
2025-10-27 | Unveiling CD177: a key player in tumors, autoimmune diseases, and inflammatory disorders.
CD177, also referred to as human neutrophil antigen NB1 or polycythemia rubra vera-1, is a glycosylphosphatidylinositol-anchored glycoprotein with a molecular weight of approximately 58-64 kDa, predominantly expressed in neutrophils, neutrophilic myelocytes, and metamyelocytes. While extensive research has focused on the role of CD177 in neutrophils, where it is implicated in transendothelial migration, cellular viability, and bactericidal activities, its functions outside of neutrophils remain largely unexplored. Under inflammatory conditions, CD177 expression on neutrophils is significantly upregulated, facilitating their migration to sites of inflammation. CD177+ neutrophils have been shown to accumulate in inflamed tissues and modulate the release of inflammatory mediators and the formation of neutrophil extracellular traps (NETs), correlating with the severity of inflammation in conditions such as inflammatory bowel disease (IBD) and acute respiratory distress syndrome (ARDS). An imbalance in CD177+ neutrophils has been identified as a critical pathogenic mechanism in vascular inflammation, tissue necrosis, and systemic lupus erythematosus (SLE). Furthermore, CD177 expression on neutrophils, epithelial cells, and regulatory T cells in solid tumors has been associated with tumor invasion, disease stage, therapeutic responses, and patient survival in various cancers, including gastric, breast, and colorectal cancer (CRC). Nevertheless, elucidating the intricate mechanisms underlying CD177's role in these diseases remains a significant challenge. In light of these findings, we present a comprehensive review of recent literature concerning the role of CD177 in tumors, inflammatory processes, and autoimmune diseases, with a particular focus on its mediating effects on neutrophil recruitment, transepithelial migration, and the activation of CD177-positive neutrophils, along with the functional implications of CD177 expression beyond neutrophils. A deeper understanding of CD177 may pave the way for the development of novel therapeutic strategies and the assessment of disease prognosis.
2024-12-10 | JAK2 mutations in polycythemia vera: from molecular origins to inflammatory pathways and clinical implications
Summary Polycythemia vera (PV) is a myeloproliferative neoplasm primarily driven by mutations in the JAK2 gene, most notably the V617F mutation, which occurs in nearly 97% of cases. This gain-of-function mutation overactivates the JAK-STAT pathway, a critical factor in developing the PV phenotype by stimulating excessive proliferation of the erythroblastic lineage. Diagnostic methods for PV focus on detecting the JAK2 mutation—primarily through polymerase chain reaction (PCR) and next-generation sequencing, which are essential for distinguishing PV from other disorders. The variant allele frequency (VAF) of JAK2 V617F also serves as an important prognostic marker, with higher VAF linked to both increased thrombotic risk and disease progression to myelofibrosis or acute leukemia. Thus, managing allele burden is central to treatment strategies. Given the genetic complexity of PV, personalized treatment approaches are essential. Current therapies focus on JAK2 signaling, with ropeginterferon alfa-2b and JAK inhibitors as primary or secondary treatments to reduce clonal expansion and control inflammation, and aspirin to prevent thrombotic events. Emerging treatments are exploring anti-inflammatory strategies, such as anti-IL-1β antibodies, and agents targeting iron metabolism to maintain hematocrit levels without phlebotomy, potentially improving quality of life. Overall, reducing JAK2 V617F burden and controlling inflammation are crucial for managing PV progression and improving patient outcomes, with ongoing research refining these therapeutic avenues to enhance long-term strategies.
2023-11-30 | [Analysis of risk factors for thromboembolism in patients with JAK2V617F gene mutation positive myeloproliferative neoplasms].
Objective: To analyze the risk factors of thrombosis in patients with JAK2V617F mutation positive myeloproliferative neoplasms (MPN). Methods: A total of 223 MPN patients with JAK2V617F mutation in the Second Hospital of Tianjin Medical University from September 2017 to May 2023 were retrospectively enrolled, including 111 males and 112 females, aged [M(Q1,Q3)] 57(21,66) years. According to the presence or absence of thromboembolism during follow-up, the patients were divided into thrombosis group (n=102) and non-thrombosis group (n=121). The clinical characteristics, laboratory characteristics, cytogenetics and other disease progression and survival of the two groups of patients were analyzed. As of March 31, 2023, the follow-up period [M (Q1, Q3)] was 6 (3, 10) years. The influencing factors of thrombosis in JAK2V617F positive MPN patients were analyzed by using the Cox risk model. Results: Among 223 JAK2V617F positive MPN patients, 144 were polycythemia vera (PV), 51 were essential thrombocythemia (ET) and 28 were primary myelofibrosis (PMF). The mutation rates of ASXL1 and BCORL1 genes in the thrombosis group were 19.6% (20/102) and 6.9% (7/102), respectively, which were higher than those in the non-thrombosis group [9.1% (11/121) and 0.8% (1/121)] (both P<0.05). The proportion of monocytes, C-reactive protein (CRP), interleukin-1β (IL)-1β, IL-8 and tumor necrosis factor-β (TNF-β) increased in the thrombosis group were higher than those in the non-thrombosis group (all P<0.05). Multivariate analysis showed that age≥60 years (HR=2.132, 95%CI: 1.376-3.303, P=0.001), history of thrombosis (HR=3.636, 95%CI: 2.121-6.202, P<0.001), ASXL1 mutation positive (HR=2.245, 95%CI: 1.093-3.231, P=0.022) and elevated TNF-β (HR=2.009, 95%CI: 1.113-3.624, P=0.021) were risk factors for thrombosis in JAK2V617F positive MPN patients. Conclusions: In addition to age, history of thrombosis and positive ASXL1 mutation, elevated TNF-β is also an influencing factor of thrombosis in JAK2V617F positive MPN patients. Intervention of inflammation may have a certain effect on the prevention and treatment of thrombosis. 目的： 分析JAK2V617F基因突变阳性骨髓增殖性肿瘤（MPN）患者发生血栓栓塞的影响因素。 方法： 回顾性纳入2017年9月至2023年5月天津医科大学第二医院223例JAK2V617F基因突变阳性MPN患者，其中男111例，女112例，年龄［M（Q1，Q3）］为57（21，66）岁。根据随访时有无血栓栓塞分为血栓组（n=102）和无血栓组（n=121）。统计两组患者临床特点、实验室特征、细胞遗传学等疾病进展及生存情况。截至2023年3月31日，随访时间［M（Q1，Q3）］为6（3，10）年。应用Cox风险模型对JAK2V617F阳性MPN患者发生血栓栓塞的影响因素进行分析。 结果： 223例JAK2V617F阳性MPN患者中，真性红细胞增多症（PV）144例，原发性血小板增多症（ET）51例，原发性骨髓纤维化（PMF）28例。血栓组患者ASXL1、BCORL1基因突变率分别为19.6%（20/102）、6.9%（7/102），均高于无血栓组的9.1%（11/121）、0.8%（1/121）（均P<0.05）。血栓组患者单核细胞、C反应蛋白（CRP）、白细胞介素（IL）-1β、IL-8、肿瘤坏死因子-β（TNF-β）升高比例均高于无血栓组（均P<0.05）。多因素分析表明，年龄≥60岁（HR=2.132，95%CI：1.376~3.303，P=0.001）、血栓栓塞史（HR=3.636，95%CI：2.121~6.202，P<0.001）、ASXL1突变阳性（HR=2.245，95%CI：1.093~3.231，P=0.022）、TNF-β升高（HR=2.009，95%CI：1.113~3.624，P=0.021）是JAK2V617F阳性MPN患者发生血栓栓塞的影响因素。 结论： 除年龄、血栓栓塞史、ASXL1突变阳性外，TNF-β升高也是JAK2V617F阳性MPN患者发生血栓栓塞的影响因素，干预炎症可能对防治血栓栓塞有一定的作用。.
other
2025-12-02 | Recent advancements in aptamer-mediated theranostics in the management of hematological disorders.
Increasing trends in the incidence rate and death rate in hematological disorders, specifically hematological malignancies, indicate the need for advancements in therapeutic approaches. Various hematological disorders include hemophilia, leukemia, lymphoma, myeloma, thrombocytopenia, sickle cell anemia, thalassemia, polycythemia vera, and aplastic anemia. Chemotherapy, cytoreductive therapy, and monoclonal antibodies are typically used for the treatment of hematological disorders. Stem cell transplantation is also performed for this purpose. However, these conventional therapeutic approaches exhibit several drawbacks, such as nonspecificity and side effects. Aptamers, being RNA or DNA oligonucleotides, selectively bind to a specific complementary molecule and serve as strong therapeutic components, offering significant theranostic implications and numerous therapeutic and diagnostic alternatives for hematological disorders. This article explains the systematic evolution of ligands through exponential enrichment, also known as the SELEX process of aptamer selection, their mechanism of action, and their wide range of applications. Moreover, it discusses the various advanced approaches for aptamer modifications to enhance their flexibility, expanding their applicability. This review article focuses on the recent updates in the application of aptamers in different hematological disorders, highlighting their potential in the therapy and diagnosis of hematological diseases.
2025-11-03 | Evaluation of the novel TMPRSS6 antisense inhibitor sapablursen for treatment of polycythemia vera: Results of the imprssion clinical trial
Abstract Background: Polycythemia vera (PV) is characterized by excessive erythrocytosis and elevated hematocrit (Hct), which is associated with increased risk of thrombotic events. Controlling Hct levels (<45%) is a key therapeutic goal to reduce thrombotic events. Sapablursen (ISIS 702843) is a liver-directed, ligand-conjugated antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6) to enhance hepcidin production thereby restricting iron availability and reduced erythrocytosis. We are reporting the topline results of the IMPRSSION study (NCT05143957), an ongoing global, open-label phase 2 trial evaluating the safety and efficacy of sapablursen for Hct control and reducing phlebotomy rate in patients with PV. Methods: Eligible patients met 2016 WHO diagnostic criteria for PV, were required to have >3 phlebotomies within six months prior to screening, including >1 phlebotomy in the last 12 weeks. There were no exclusions for HCT prior to randomization. Patients received monthly subcutaneous doses of sapablursen in Cohort A (high dose) or Cohort B (low dose), during a 37-week treatment period. The primary efficacy endpoint was the reduction in the frequency of phlebotomy during the last 20 weeks of the treatment period (Week 17-37) compared to baseline (defined as the mean weekly phlebotomy rate during the six months prior to screening through the first dose of sapablursen). Phlebotomy was performed when Hct levels were ≥45% or at the investigator's discretion, confirmation of Hct was not required for phlebotomy. Serial assessments of serum hepcidin, TSAT and ferritin were conducted. The 10-item Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) assessed the change in symptoms from baseline to Week 37. Results: Forty-nine (49) patients received at least one dose of sapablursen (full analysis set) in either Cohort A (n=32) or Cohort B (n=17). The median age was 61 years, 40 (82%) were male, and 29 (59%) classified as high risk. The primary endpoint was met at both dose levels. The weekly phlebotomy rate (mean±SD) decreased from baseline of 0.15±0.07 (~7.8/yr) to 0.05±0.09 (~2.6/yr) during the primary endpoint window (Week 17-37) in Cohort A (n=32, p<0.0001; 95%CI, -0.13, -0.07), and from 0.17±0.07 (~8.9/yr) to 0.07±0.07 (~3.6/yr) in Cohort B (n=17, p=0.0001; 95%CI, -0.14, -0.06). The mean MPN-SAF-TSS was reduced at Week 37 by 32% in Cohort A (change from baseline LSM -6.2, p=0.005) and 11% in Cohort B (change from baseline LSM -2.7, p=0.344). The proportion of patients with Hct control (<45%) without phlebotomy from week 17 to 37 in Cohort A and B was 53% (17/32) and 35% (6/17), respectively. Serum hepcidin was increased from baseline values of 0.25±0.6 to 5.05±4.7 nM at Week 13 in Cohort A (p<0.0001) and from 0.68±1.7 to 2.06±3.6 nM in Cohort B (p=0.0142). A sustained low TSAT was observed between Weeks 17-37 (6.0±2.1% and 5.5±2.0% in Cohort A and 8.9±5.0% and 7.0±3.4% in Cohort B). Serum ferritin increased over time from 18±22 ng/mL and 28±58 ng/mL at baseline in Cohort A and B, respectively, to 44±47 ng/mL and 41±85 ng/mL at Week 37, respectively. Sapablursen was generally safe and well-tolerated. The incidence of injection site reactions was 12.2% (6/49). Injection site reactions did not recur following multiple injections, were not progressive and resolved spontaneously. There was one death on study due to transformation to AML which was deemed as not related to the study drug. Conclusions: Treatment of PV patients with sapablursen increased serum hepcidin, controlled Hct, reduced phlebotomy need and improved quality of life in a dose-dependent manner. These findings highlight the potential of sapablursen as a therapeutic approach in PV and support further development.
2024-01-22 | Idiopathic erythrocytosis: a germline disease?
Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, < 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.
2022-10-25 | The accumulation of miR-125b-5p is indispensable for efficient erythroblast enucleation.
Erythroblast enucleation is a precisely regulated but not clearly understood process. Polycythemia shows pathological erythroblast enucleation, and we discovered a low miR-125b-5p level in terminal erythroblasts of patients with polycythemia vera (PV) compared to those of healthy controls. Exogenous upregulation of miR-125b-5p levels restored the enucleation rate to normal levels. Direct downregulation of miR-125b-5p in mouse erythroblasts simulated the enucleation issue found in patients with PV, and miR-125b-5p accumulation was found in enucleating erythroblasts, collectively suggesting the importance of miR-125b-5p accumulation for erythroblast enucleation. To elucidate the role of miR-125b-5p in enucleation, gain- and loss-of-function studies were performed. Overexpression of miR-125b-5p improved the enucleation of erythroleukemia cells and primary erythroblasts. Infused erythroblasts with higher levels of miR-125b-5p also exhibited accelerated enucleation. In contrast, miR-125b-5p inhibitors significantly suppressed erythrocyte enucleation. Intracellular imaging revealed that in addition to cytoskeletal assembly and nuclear condensation, miR-125b-5p overexpression resulted in mitochondrial reduction and depolarization. Real-time PCR, western blot analysis, luciferase reporter assays, small molecule inhibitor supplementation and gene rescue assays revealed that Bcl-2, as a direct target of miR-125b-5p, was one of the key mediators of miR-125b-5p during enucleation. Following suppression of Bcl-2, the activation of caspase-3 and subsequent activation of ROCK-1 resulted in cytoskeletal rearrangement and enucleation. In conclusion, this study is the first to reveal the pivotal role of miR-125b-5p in erythroblast enucleation.
2021-10-26 | CRISPR/Cas9 mediated CXCL4 knockout in human iPS cells of polycythemia vera patient with JAK2 V617F mutation.
The chemokine CXCL4/platelet factor 4 (PF4) gene, a key player in myelofibrosis, was knocked out by CRISPR/Cas9 in induced pluripotent stem cells (iPS cells) of a polycythemia vera (PV) patient with JAK2 V617F mutation. Two CXCL4KO iPS cell lines with and without JAK2 V617F mutation (UKAi002-B-1 and UKAi002-A-1, respectively) were generated. CXCL4KO iPS cells showed deletion of exon 1 and complete loss of CXCL4 protein. Pluripotency of iPS cells was confirmed by expression of pluripotency markers and trilineage differentiation. CXCL4KO iPS cells are expected to provide a valuable tool for investigating the role of CXCL4 in human diseases.
small molecules
2026-08-11 | First Philippine report of myeloproliferative neoplasms with concurrent JAK2 and BCR::ABL1 mutations.
Myeloproliferative neoplasms (MPNs) are broadly classified into BCR::ABL1-positive chronic myeloid leukaemia (CML) and BCR::ABL1-negative subtypes such as polycythaemia vera (PV), essential thrombocythaemia and primary myelofibrosis. Although traditionally considered mutually exclusive, rare cases of coexisting BCR::ABL1 rearrangement and Janus kinase 2 (JAK2) mutation have increasingly been recognised.We report the first Philippine case series of three patients with concurrent CML and JAK2-positive MPNs. Two patients developed PV 6-9 years after the initial diagnosis of CML despite ongoing tyrosine kinase inhibitor (TKI) therapy and molecular response, while a third patient had persistent thrombocytosis and was later found to have a concomitant JAK2-mutated MPN with fibrotic marrow features after 4 years.Compared with previously reported cases, our series demonstrates similarly delayed emergence of JAK2-mutated clones while highlighting real-world challenges in TKI intolerance, sequential TKI use and the need for combined cytoreductive strategies in a resource-limited setting.
2026-08-09 | The thrombopoietin receptor in myeloproliferative neoplasms: A unifying mechanism of disease pathogenesis and therapeutic targeting.
The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis, are clonal hematopoietic stem cell disorders unified by constitutive thrombopoietin receptor (MPL) signaling. All 3 MPN driver mutations, JAK2, CALR, and MPL, converge on enhanced MPL signaling, establishing the thrombopoietin (TPO)/MPL axis as the central molecular hub linking clonal hematopoiesis to the cardinal manifestations of MPN, including thrombosis, hemorrhage, and fibrotic progression. As the principal regulator of hematopoietic stem cell maintenance and megakaryopoiesis and a key mediator of platelet priming, the TPO/MPL axis links stem cell biology to thromboinflammation and disease progression. This review summarizes the physiologic functions of the TPO/MPL axis, its dysregulation in MPN, and the downstream mechanisms linking aberrant MPL signaling to thrombosis, hemorrhage, and fibrotic progression. We further highlight recent advances in our understanding of TPO/MPL signaling in platelet biology, including its roles in platelet activation, metabolism, and thromboinflammation, and discuss emerging therapeutic strategies targeting the TPO/MPL pathway with the goal of simultaneously reducing thrombohemorrhagic complications, limiting fibrotic progression, and diminishing the malignant stem cell clone.
2026-08-08 | Case Report: Polycythemia vera presenting as persistent unexplained low-grade fever.
Persistent fever as an initial manifestation of polycythemia vera (PV) is uncommon and may lead to diagnostic delay. We report a 72-year-old woman with recurrent low-grade fever for 1 month, with a maximum temperature not exceeding 38.0 °C. Although this presentation did not meet the classic fever-of-unknown-origin temperature threshold, it prompted an FUO-like diagnostic evaluation because routine infectious and autoimmune investigations were unrevealing and empirical antimicrobial therapy was ineffective. Laboratory evaluation revealed elevated hemoglobin and hematocrit levels, accompanied by leukocytosis and initially high-normal platelet counts that later progressed to thrombocytosis. Chest CT/PET-CT showed diffuse ground-glass/interstitial pulmonary changes; active bacterial pneumonia was considered unlikely based on the absence of respiratory symptoms, procalcitonin at the upper limit of the normal range, negative cultures and sputum smears, and absence of FDG-avid pulmonary consolidation, although a concomitant viral or noninfectious inflammatory pulmonary process could not be completely excluded. Bone marrow biopsy showed hypercellular marrow with panmyelosis and megakaryocytic proliferation, and molecular testing identified a JAK2 V617F mutation with a high allele burden. The diagnosis of PV was established based on the 5th edition of the World Health Organization (WHO) diagnostic criteria. The patient was treated with hydroxyurea and aspirin, resulting in gradual resolution of fever and improvement in hematological parameters. This case highlights that PV should be considered in the differential diagnosis of persistent unexplained low-grade fever when erythrocytosis and other myeloproliferative features are present, while alternative pulmonary causes should be assessed carefully.
2026-08-04 | Acute erythroid leukaemia transformation in polycythaemia vera with leukemic involvement in liver and ascites.
Polycythaemia vera (PV) may rarely evolve into acute erythroid leukaemia (AEL). We herein report a known case of JAK2 p. V617F mutated PV presenting with progressive hepatosplenomegaly, abdominothoracic lymphadenopathy, ascites and various haematological derangements. Rapid diagnostic work-up revealed extensive marrow, hepatic and ascitic fluid infiltration by many CD71+, LMO2+ and p53+ proerythroblasts. Next generation sequencing showed TP53, ASXL1 and TET2 gene mutations. A chemotherapeutic regimen of ruxolitinib, azacitidine and venetoclax was initiated. A comprehensive review of the English literature emphasises clinical, morphologic, immunophenotypic and genetic characteristics of AEL transformation in PV.
2026-08-03 | [Disappearance of del (7q) with lenalidomide in myelofibrosis complicated with multiple myeloma].
Lenalidomide, an immune-modulatory drug, is used to treat multiple myeloma (MM). Lenalidomide has also been investigated as a treatment for myelofibrosis (MF); however, its efficacy in this setting has not been established. We report a case of secondary MF progressing from polycythemia vera (PV) that had the poor prognostic factor del (7q) and concurrent MM, in which del (7q) disappeared and MF improved after treatment with lenalidomide. A 69-year-old woman presented to our hospital with PV in March 2022. Bone marrow examination revealed grade 2 fibrosis. The diagnosis was secondary MF progressing from PV, with JAK2 V617F and del (7q), along with IgG-κ monoclonal gammopathy of undetermined significance (MGUS). In May 2023, the appearance of new bone lesions indicated progression of MGUS to MM. Treatment with lenalidomide plus dexamethasone achieved a partial response. After this treatment, del (7q) disappeared and MF improved. The efficacy of lenalidomide in MF with del (7q) has never been reported. This case shows that lenalidomide may improve the prognosis of MF with del (7q).
cell therapies
2026-07-30 | Evaluation of the efficacy of erythrocytapheresis and phlebotomy in the treatment of polycythemia.
Systematic comparison of the efficacy and safety of erythrocytapheresis and phlebotomy. A retrospective analysis of 108 polycythemia patients categorized into four treatment groups: 1, 2, or 3 sessions of phlebotomy, and 1 session of erythrocytapheresis. The primary outcome was HGB change. One-way analysis of variance (ANOVA), Kruskal-Wallis H test, t-tests, and linear regression were used to compare efficacies and identify predictive factors, with subgroup analyses for polycythemia vera (PV) and high-altitude polycythemia (HAPC). Linear trend analysis was performed to evaluate the dose-response relationship.The references cited in this article were retrieved through the PUBMED database. A significant difference in HGB change was observed among four groups. 3 sessions of phlebotomy were superior to 1 and 2 sessions. 1 session of erythrocytapheresis achieved comparable HGB change to 2-3 phlebotomy sessions. Linear trend analysis confirmed HGB change increased with phlebotomy sessions. In the PV subgroup, baseline HGB and female gender were predictors of HGB change. In the HAPC subgroup, only baseline HGB was a significant predictor. 2-3 sessions of phlebotomy are non-inferior to 1 session of erythrocytapheresis in efficacy, with higher safety and cost-effectiveness, and baseline HGB is a universal predictor of therapeutic efficacy.
2025-05-28 | CRISPR/Cas9-Based Modeling of JAK2 V617F Mutation in K562 Cells Reveals Enhanced Proliferation and Sensitivity to Therapeutic Agents.
The Janus kinase 2 (JAK2) protein fulfills an important role in hematopoiesis via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, as it provides the genetic driver of BCR::ABL1-negative myeloproliferative neoplasms (MPNs), which are clinically manifested as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The most common cause of MPNs is the mutation of JAK2 V617F in the JAK2 gene, which results in increased cell proliferation. However, both the pathogenesis and treatment regimen of BCR::ABL1-negative MPNs remain poorly understood. The aim of the present study was to establish K562 cell lines with a point mutation in exon 14 (JAK2p.V617F) using CRISPR/Cas9 technology. The modified JAK2 V617F cell lines were examined for the gene mutation using droplet digital PCR (DDPCR), and the presence of the mutation was confirmed by DNA sequencing. Modified cells were characterized by measuring JAK2 gene expression and the extent of cell proliferation. Interferon α2a (IFN-α2a) and arsenic trioxide were also administered to the cells to explore their potential effects. The JAK2 V617F-mutated cells were found to exhibit a higher level of JAK2 gene expression compared with the wild type. Interestingly, a significant increase in the proliferation rate was observed with the modified cells compared with the wild type cells (p < 0.001), as assessed from the JAK2 gene expression levels. Furthermore, the treatments with IFN-α2a and arsenic trioxide led to the preferential suppression of the cell proliferation rate of the K562 expressing mutant JAK2 cells compared with the wild type cells, and this suppression occurred in a dose-dependent manner(p < 0.01). Moreover, the modified cells were able to differentiate into megakaryocyte-like cells following stimulation with phorbol 12 myristate 13 acetate (PMA). Taken together, the results of the present study have shown that the CRISPR/Cas9-modified JAK2 V617F model may be used as a disease model in the search of novel therapies for MPNs.
2025-05-24 | Clinical application of erythrocytapheresis in the treatment of erythrocytosis.
This study aimed to clarify the clinical utility of erythrocytapheresis as a treatment for erythrocytosis, including polycythemia vera and secondary erythrocytosis. A retrospective analysis was conducted on 83 patients (84.34 % male, mean age 49.66 years (16.23 years)) who underwent a total of 104 erythrocytapheresis sessions between September 2021 and April 2025. The key parameters measured included the depleted red blood cell (RBC) volume, the hemoglobin (HB) and hematocrit (Hct) reductions, and adverse reactions. Erythrocytapheresis significantly reduced the post-treatment RBC counts (25.22 %), the HB (25.19 %) level and the Hct (23.62 %), the white blood cell counts, (23.37 %) and the platelet counts (8.38 %) (all p < 0.05). The median depleted RBC volume was 1405.5 mL (range 1011.75-1677.5 mL). The median post-treatment target Hct was 40 % (range 40-45 %). The mean post-treatment Hct was in fact 47.57 % (6.54 %), which was higher than the target, and the mean Hct error ratio was 14.23 % (12.95 %). When the replacement solution was physiological saline, an adverse reaction (hypotension) occurred during 4.81 % of the 104 erythrocytapheresis sessions, but only in patients with a depleted RBC volume/weight (D/W) ≥ 25 mL/kg. No significant differences were observed between the Spectra Optia and COM.TEC blood cell separators. Erythrocytapheresis effectively reduces the RBC mass in patients with erythrocytosis.In rough terms, the post-treatment target Hct = the post-treatment Hct × 0.88, our research team has officially designated this formula as the 'Southwest Formula'. In the future, we will continue to expand the sample size to enhance the precision of this formula and better guide the clinical application of erythrocytapheresis.
2024-08-31 | Impact of Phlebotomy on Quality of Life in Low-Risk Polycythemia Vera.
Polycythemia vera is an indolent myeloproliferative disorder that predisposes patients to venous and arterial thrombosis and can transform into myelofibrosis and acute myeloid leukemia. Consistent phlebotomy prevents life-threatening cerebrovascular and coronary artery disease and prolongs survival in low-risk polycythemia vera (patients under 60 years without thrombosis). However, despite its effectiveness in preventing serious complications, phlebotomy does not necessarily enhance the quality of life (QoL). This review assesses QoL issues associated with low-risk PV, explores alternative management strategies such as erythrocytapheresis, and discusses the roles of hydroxyurea, peginterferon, ruxolitinib, and other novel agents in potentially improving disease management and patient outcomes.
2024-06-17 | A comparison between erythrocytapheresis and venesection for the treatment of JAK2-mutated polycythaemia.
JAK2-mutated polycythaemia vera (PV) is associated with reduced survival because of thrombotic events and haematological disease transformation. Therapeutic venesection has traditionally been used to lower haematocrit, but the technique of erythrocytapheresis has emerged over the last decade. To compare erythrocytapheresis with venesection as treatment for PV by assessing medical efficacy and financial viability. One hundred sixteen patients with PV who received red cell depletion therapy at Barwon Health between 2014 and 2021 were identified. The haematocrit drop after each session, interval between treatment times and number of sessions required to achieve a haematocrit <0.45 were compared with an independent t test. Thrombosis rates were compared with Pearson's chi-squared test. Cost-funding analysis was done by assessing the Weighted Inlier Equivalent Separation and National Weighted Activity Unit funding models. Patients treated with erythrocytapheresis achieved a greater haematocrit drop each treatment session (0.075 vs 0.03, P < 0.01), required fewer sessions to achieve a haematocrit <0.45 (1 vs 4, P < 0.01) and experienced fewer thrombotic complications (8.7% vs 32.1%, P = 0.02) than those treated with venesection. Cost-funding analysis demonstrated that erythrocytapheresis was more financially viable with a surplus of AU$297 per session compared to a deficit of AU$176 with venesection. Even if funding for venesection is increased, the cost of erythrocytapheresis may be mitigated by a lower number of procedures required per year (3.8 vs 5.3, P < 0.01). Erythrocytapheresis is more efficacious than venesection for the treatment of PV and is accompanied by rapid reductions in haematocrit and reduced thrombotic complications.
proteins
2026-08-07 | Ropeginterferon alfa-2b in Polycythemia Vera: A systematic review and meta-analysis.
Ropeginterferon alfa-2b, a novel monopegylated interferon with improved pharmacokinetics, has emerged as a promising cytoreductive agent for managing polycythemia vera (PV). Despite increasing adoption, evidence synthesis of its efficacy and safety compared to standard care remains limited. The manuscript aimed to evaluate the efficacy of ropeginterferon alfa-2b in comparison to standard treatment options, including hydroxyurea and phlebotomy, in achieving complete hematologic response, partial molecular response (PMR), and reducing JAK2V617F allele burden in patients with PV. A systematic search of 4 databases was conducted up to April 2025, following PRISMA 2020 guidelines. Randomized controlled trials (RCTs) comparing ropeginterferon alfa-2b with standard therapies in PV patients were included. Meta-analyses were performed using random-effects models to derive odds ratios for dichotomous outcomes and mean differences (MDs) for continuous outcomes. Sensitivity and subgroup analyses were conducted, and risk of bias was assessed using RoB 2.0. Three RCTs comprising 522 patients were analyzed. Ropeginterferon alfa-2b showed no statistically significant advantage overall or over hydroxyurea for complete hematological response (CHR), PMR, or JAK2 allele burden reduction. However, subgroup analyses revealed significant benefits over phlebotomy alone in all 3 outcomes: CHR (odds ratio [OR] 3.05; 95% confidence interval [CI]: 1.36-6.80; P = .007), PMR (OR 36.34; 95% CI: 2.11-625.93; P = .01), and allele burden reduction (MD -13.70; 95% CI: -19.24 to -8.16; P < .00001). Ropeginterferon alfa-2b demonstrates no statistically significant difference compared to hydroxyurea, but gives better outcomes over phlebotomy in short-term efficacy for PV management. Its favorable molecular and hematologic outcomes support its role as a disease-modifying therapy, particularly in low-risk patients. However, larger and longer-term trials are needed to confirm these benefits across broader populations.
2026-07-16 | Successful Topical Treatment of Hydroxyurea-Induced Ulcers Without Drug Discontinuation: A Case Report.
Hydroxyurea, an antineoplastic agent, is widely used to treat essential thrombocythemia and polycythemia vera. Although hydroxyurea-induced skin ulcers are uncommon, they are a recognized long-term adverse effect. Current management generally recommends discontinuation of hydroxyurea as the mainstay of treatment; however, drug withdrawal may aggravate the underlying hematologic disease. We report a case of bilateral medial malleolar ulcers associated with hydroxyurea therapy in a 65-year-old man with essential thrombocythemia, who showed marked improvement after two months of topical treatment with recombinant bovine basic fibroblast growth factor (rb-bFGF) gel, without discontinuation of hydroxyurea. Complete healing was confirmed at 25-month follow-up, while hematologic disease control was maintained. This case suggests that localized wound care with topical rb-bFGF may represent a feasible therapeutic option in selected patients when hydroxyurea discontinuation is not feasible.
2026-05-03 | Hematologic and molecular response to ropeginterferon alfa-2b in patients with polycythemia vera: a systematic review and meta-analysis.
Ropeginterferon alfa-2b is an interferon used in the treatment of myeloproliferative neoplasms, particularly polycythemia vera. Its efficacy in achieving hematologic and molecular responses has been demonstrated in clinical trials, but pooled data on long-term outcomes and sustained response remain limited. This systematic review and meta-analysis aimed to evaluate the hematologic and molecular response over 36 months. PubMed, Scopus, Science Direct, and Google Scholar databases were searched to identify studies reporting hematologic and molecular responses to ropeginterferon alfa-2b. Studies were included if they provided data on complete hematologic response (CHR) and JAK2V617F variant allele frequency (VAF) reduction. Pooled proportions and mean reductions were calculated using random-effects models. The pooled proportion of CHR increased progressively from 0.19 (95% CI: 0.04-0.57) at 3 months to 0.73 (95% CI: 0.17-0.97) at 36 months. Molecular response, measured by VAF reduction, deepened over time from - 7.33 (95% CI: -9.85 to -4.81) at 3 months to -54.90 (95% CI: -65.61 to -43.99) at 36 months. Subgroup analyses revealed significant variability in response rates, particularly in early follow-up periods. Ropeginterferon alfa-2b achieves significant and sustained hematologic and molecular responses over 36 months. This makes it a promising treatment for polycythemia vera. While variability in early responses needs further investigation, the sustained long-term efficacy compared to hydroxyurea supports its use in clinical practice. Future studies should focus on identifying predictors of response and optimizing treatment protocols to maximize patient outcomes.
2026-04-11 | Ropeginterferon dose-escalation strategies in polycythemia vera: a systematic review and meta-analysis
Abstract Background Ropeginterferon alfa-2b is increasingly used as a long-acting interferon therapy for polycythemia vera (PV), providing hematologic and molecular benefits. However, clinical studies have implemented different dose-escalation strategies, and their impact on outcomes has not been systematically evaluated. Methods A systematic search of PubMed, Embase, and the Cochrane Library (September 24, 2025) identified studies reporting clinical outcomes of ropeginterferon in PV. Nine studies met eligibility criteria. Two reviewers independently extracted data, and meta-analyses were conducted using random-effects models. Subgroup analyses compared slow dose-up (SDU) and rapid dose-up (RDU) regimens at 1-, 2-, and 3-year follow-up when available. Results The pooled 1-year complete hematologic response (CHR) rate was 0.59 (95% CI, 0.47–0.71). RDU regimens yielded significantly higher CHR than SDU at both 1 year (0.67 vs. 0.41; p < 0.001) and 2 years (0.75 vs. 0.63; p = 0.038). Molecular response (MR) also favored RDU at 1 year (0.59 vs. 0.36; p < 0.001), with differences diminishing at 2 years. The pooled 1-year reduction in JAK2 V617F allele burden was − 22.2% (95% CI, − 34.2% to − 10.2%; p < 0.001). Safety outcomes were favorable, with low rates of thrombosis (4%), serious adverse events (5%), and treatment discontinuation (7%). Conclusions Ropeginterferon alfa-2b provides meaningful hematologic and molecular responses with an acceptable safety profile in PV. Rapid dose-escalation facilitates earlier CHR and MR without increasing toxicity, suggesting titration speed as an important determinant of early treatment optimization.
2026-04-09 | A paradigm shift in the treatment of patients with polycythemia vera. The initial early use of recombinant interferon-alpha.
During the past 35 years, single-arm studies documented the efficacy and safety of recombinant interferon alpha (rIFNα) for treating polycythemia vera (PV). In some patients, 2-5 years of disease-modifying treatment resulted in symptom relief, regression of splenomegaly, normalization of abnormal blood counts and marrow morphology, and sustained JAK2V617F molecular remission. The PROUD-CONTI study showed the superiority of rIFNα compared to hydroxyurea (HU), which led to the European Medicines Agency approval in 2019 of ropeginterferon alpha-2b ("ropegIFN") for ELN-defined high-risk PV patients. In 2021, the Food and Drug Administration (USA) gave unrestricted approval, except for pregnant PV patients. The Low-PV randomized trial established the superiority of ropegIFN compared to phlebotomy-only (PHLEB-O) in ELN-defined low-risk patients. Nevertheless, worldwide, HU remains the cytoreductive drug most often used; maintenance PHLEB-O is still endorsed as maintenance therapy by some hematologists. The National Comprehensive Cancer Network (NCCN, USA) approved ropegIFN as a II-A recommendation for ELN-defined low and high-risk disease; the ELN suggested criteria for using rIFNα in low-risk patients if certain issues developed after PHLEB-O, including more symptoms, progressive splenomegaly, significant leukocytosis, thrombocytosis, or inadequate hematocrit control. These issues are important because even low-risk patients are at increased thrombotic risk, estimated at 2 to 3 times that of the general population. Moreover, as PV progresses, the development of myelofibrosis is the leading cause of morbidity, perhaps abetted by PHLEB-O. Here, we review recent progress in the treatment of PV with rIFNα and discuss our rationales and perspectives for, and the endorsement of the initial treatment with rIFNα of both low and high-risk PV patients, unless a contraindication exists to its use.
antibodies
2026-04-29 | A Phase 1 Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study of DISC-3405, a Novel Recombinant Humanized Monoclonal Antibody Targeting TMPRSS6, in Adult Healthy Volunteers.
Hepcidin is the central regulator of iron homeostasis, controlling iron sequestration and dietary iron absorption. Transmembrane serine protease 6 (TMPRSS6) suppresses hepcidin via the bone morphogenetic protein/small mothers against decapentaplegic (BMP/SMAD) pathway by cleaving the co-receptor hemojuvelin. DISC-3405 is a novel humanized monoclonal antibody that enhances hepcidin expression by inhibiting TMPRSS6, thereby promoting iron restriction. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of DISC-3405 or placebo in 56 healthy participants. DISC-3405 (37.5 to 300 mg) or placebo was administered subcutaneously (SC) or intravenously (IV). DISC-3405 was well tolerated. No deaths, serious adverse events, or participant discontinuations occurred. Most treatment-emergent adverse events were Grade 1 (mild) in severity, with 2 participants reporting Grade 2 (moderate) events following single dosing and no Grade 3/4 (severe/life-threatening) events reported. Median time to maximum plasma concentration was ≈96 to 168 h. Elimination half-life rose from 130 h at 37.5 mg to 265 h at 300 mg, with a clinically relevant half-life of ≈11 days. Absolute bioavailability was 39.7% (75 mg SC vs. IV). Minor accumulation occurred with repeat 4-week dosing of two doses, and PK was greater than dose proportional. DISC-3405 increased hepcidin-25 and reduced serum iron and transferrin saturation across dose levels. Single and repeated dosing of DISC-3405 produced reductions in reticulocyte hemoglobin, hemoglobin, and hematocrit. Overall, DISC-3405 was well tolerated with PK/PD data supporting further development for patients who could benefit from iron restriction, such as those with polycythemia vera.
2025-11-30 | Mesenchymal stromal cells secretory pattern contributes to oncoinflammatory bone marrow microenvironment in polycythemia vera.
Polycythemia vera is a myeloproliferative neoplasm marked by an increased proliferation of erythroid mature and precursors cells in bone marrow and peripheral blood. The pathophysiology is linked to the presence of the JAK2 driver mutation, epigenetic deregulation, and alterations in the bone marrow hematopoietic niche. Multipotent mesenchymal stromal cells (MSC) in the bone marrow, which are crucial for maintenance and development of hematopoietic stem cells, play a role in the communication between neoplastic cells and resident bone marrow cells by releasing various mediators that either suppress or promote tumor progression. These mediators include several essential immunomodulatory molecules, pro-angiogenic and growth factors. We hypothesized that MSC from polycythemia vera patients (Patient Group) would exhibit distinct properties compared to those from healthy donors (Control Group), thereby influencing the hematopoietic niche and contributing to disease pathogenesis. This study characterized MSC from patients, focusing on their secretory, proteomic, and phenotypic properties. MSC from the Patient and Control Groups had similar immunophenotypes and multipotentiality. However, MSC from the Patient Group exhibited reduced immunomodulatory properties, and released distinct soluble immune and angiogenic mediators when compared with the Control Group. Global proteomic analysis revealed that MSC from patients presented upregulated expressions of FAM175B, VP526A, CTTN, MAP4, BAX, and TPD52L2 but a downregulated TNC expression. These results indicate that MSC contribute to the inflammation pattern in the hematopoietic niche. The secretory and proteomic profile of MSC from patients, indicate that these cells may influence immune cell function, induce neoangiogenesis, and alter cell-to-cell interactions within the bone marrow, thereby fostering a pro-tumor microenvironment and favoring disease pathogenesis. These findings highlight the potential of targeting MSC-mediated pathways as a therapeutic strategy in polycythemia vera.
2025-10-27 | Unveiling CD177: a key player in tumors, autoimmune diseases, and inflammatory disorders.
CD177, also referred to as human neutrophil antigen NB1 or polycythemia rubra vera-1, is a glycosylphosphatidylinositol-anchored glycoprotein with a molecular weight of approximately 58-64 kDa, predominantly expressed in neutrophils, neutrophilic myelocytes, and metamyelocytes. While extensive research has focused on the role of CD177 in neutrophils, where it is implicated in transendothelial migration, cellular viability, and bactericidal activities, its functions outside of neutrophils remain largely unexplored. Under inflammatory conditions, CD177 expression on neutrophils is significantly upregulated, facilitating their migration to sites of inflammation. CD177+ neutrophils have been shown to accumulate in inflamed tissues and modulate the release of inflammatory mediators and the formation of neutrophil extracellular traps (NETs), correlating with the severity of inflammation in conditions such as inflammatory bowel disease (IBD) and acute respiratory distress syndrome (ARDS). An imbalance in CD177+ neutrophils has been identified as a critical pathogenic mechanism in vascular inflammation, tissue necrosis, and systemic lupus erythematosus (SLE). Furthermore, CD177 expression on neutrophils, epithelial cells, and regulatory T cells in solid tumors has been associated with tumor invasion, disease stage, therapeutic responses, and patient survival in various cancers, including gastric, breast, and colorectal cancer (CRC). Nevertheless, elucidating the intricate mechanisms underlying CD177's role in these diseases remains a significant challenge. In light of these findings, we present a comprehensive review of recent literature concerning the role of CD177 in tumors, inflammatory processes, and autoimmune diseases, with a particular focus on its mediating effects on neutrophil recruitment, transepithelial migration, and the activation of CD177-positive neutrophils, along with the functional implications of CD177 expression beyond neutrophils. A deeper understanding of CD177 may pave the way for the development of novel therapeutic strategies and the assessment of disease prognosis.
2024-12-10 | JAK2 mutations in polycythemia vera: from molecular origins to inflammatory pathways and clinical implications
Summary Polycythemia vera (PV) is a myeloproliferative neoplasm primarily driven by mutations in the JAK2 gene, most notably the V617F mutation, which occurs in nearly 97% of cases. This gain-of-function mutation overactivates the JAK-STAT pathway, a critical factor in developing the PV phenotype by stimulating excessive proliferation of the erythroblastic lineage. Diagnostic methods for PV focus on detecting the JAK2 mutation—primarily through polymerase chain reaction (PCR) and next-generation sequencing, which are essential for distinguishing PV from other disorders. The variant allele frequency (VAF) of JAK2 V617F also serves as an important prognostic marker, with higher VAF linked to both increased thrombotic risk and disease progression to myelofibrosis or acute leukemia. Thus, managing allele burden is central to treatment strategies. Given the genetic complexity of PV, personalized treatment approaches are essential. Current therapies focus on JAK2 signaling, with ropeginterferon alfa-2b and JAK inhibitors as primary or secondary treatments to reduce clonal expansion and control inflammation, and aspirin to prevent thrombotic events. Emerging treatments are exploring anti-inflammatory strategies, such as anti-IL-1β antibodies, and agents targeting iron metabolism to maintain hematocrit levels without phlebotomy, potentially improving quality of life. Overall, reducing JAK2 V617F burden and controlling inflammation are crucial for managing PV progression and improving patient outcomes, with ongoing research refining these therapeutic avenues to enhance long-term strategies.
2023-11-30 | [Analysis of risk factors for thromboembolism in patients with JAK2V617F gene mutation positive myeloproliferative neoplasms].
Objective: To analyze the risk factors of thrombosis in patients with JAK2V617F mutation positive myeloproliferative neoplasms (MPN). Methods: A total of 223 MPN patients with JAK2V617F mutation in the Second Hospital of Tianjin Medical University from September 2017 to May 2023 were retrospectively enrolled, including 111 males and 112 females, aged [M(Q1,Q3)] 57(21,66) years. According to the presence or absence of thromboembolism during follow-up, the patients were divided into thrombosis group (n=102) and non-thrombosis group (n=121). The clinical characteristics, laboratory characteristics, cytogenetics and other disease progression and survival of the two groups of patients were analyzed. As of March 31, 2023, the follow-up period [M (Q1, Q3)] was 6 (3, 10) years. The influencing factors of thrombosis in JAK2V617F positive MPN patients were analyzed by using the Cox risk model. Results: Among 223 JAK2V617F positive MPN patients, 144 were polycythemia vera (PV), 51 were essential thrombocythemia (ET) and 28 were primary myelofibrosis (PMF). The mutation rates of ASXL1 and BCORL1 genes in the thrombosis group were 19.6% (20/102) and 6.9% (7/102), respectively, which were higher than those in the non-thrombosis group [9.1% (11/121) and 0.8% (1/121)] (both P<0.05). The proportion of monocytes, C-reactive protein (CRP), interleukin-1β (IL)-1β, IL-8 and tumor necrosis factor-β (TNF-β) increased in the thrombosis group were higher than those in the non-thrombosis group (all P<0.05). Multivariate analysis showed that age≥60 years (HR=2.132, 95%CI: 1.376-3.303, P=0.001), history of thrombosis (HR=3.636, 95%CI: 2.121-6.202, P<0.001), ASXL1 mutation positive (HR=2.245, 95%CI: 1.093-3.231, P=0.022) and elevated TNF-β (HR=2.009, 95%CI: 1.113-3.624, P=0.021) were risk factors for thrombosis in JAK2V617F positive MPN patients. Conclusions: In addition to age, history of thrombosis and positive ASXL1 mutation, elevated TNF-β is also an influencing factor of thrombosis in JAK2V617F positive MPN patients. Intervention of inflammation may have a certain effect on the prevention and treatment of thrombosis. 目的： 分析JAK2V617F基因突变阳性骨髓增殖性肿瘤（MPN）患者发生血栓栓塞的影响因素。 方法： 回顾性纳入2017年9月至2023年5月天津医科大学第二医院223例JAK2V617F基因突变阳性MPN患者，其中男111例，女112例，年龄［M（Q1，Q3）］为57（21，66）岁。根据随访时有无血栓栓塞分为血栓组（n=102）和无血栓组（n=121）。统计两组患者临床特点、实验室特征、细胞遗传学等疾病进展及生存情况。截至2023年3月31日，随访时间［M（Q1，Q3）］为6（3，10）年。应用Cox风险模型对JAK2V617F阳性MPN患者发生血栓栓塞的影响因素进行分析。 结果： 223例JAK2V617F阳性MPN患者中，真性红细胞增多症（PV）144例，原发性血小板增多症（ET）51例，原发性骨髓纤维化（PMF）28例。血栓组患者ASXL1、BCORL1基因突变率分别为19.6%（20/102）、6.9%（7/102），均高于无血栓组的9.1%（11/121）、0.8%（1/121）（均P<0.05）。血栓组患者单核细胞、C反应蛋白（CRP）、白细胞介素（IL）-1β、IL-8、肿瘤坏死因子-β（TNF-β）升高比例均高于无血栓组（均P<0.05）。多因素分析表明，年龄≥60岁（HR=2.132，95%CI：1.376~3.303，P=0.001）、血栓栓塞史（HR=3.636，95%CI：2.121~6.202，P<0.001）、ASXL1突变阳性（HR=2.245，95%CI：1.093~3.231，P=0.022）、TNF-β升高（HR=2.009，95%CI：1.113~3.624，P=0.021）是JAK2V617F阳性MPN患者发生血栓栓塞的影响因素。 结论： 除年龄、血栓栓塞史、ASXL1突变阳性外，TNF-β升高也是JAK2V617F阳性MPN患者发生血栓栓塞的影响因素，干预炎症可能对防治血栓栓塞有一定的作用。.
other
2025-12-02 | Recent advancements in aptamer-mediated theranostics in the management of hematological disorders.
Increasing trends in the incidence rate and death rate in hematological disorders, specifically hematological malignancies, indicate the need for advancements in therapeutic approaches. Various hematological disorders include hemophilia, leukemia, lymphoma, myeloma, thrombocytopenia, sickle cell anemia, thalassemia, polycythemia vera, and aplastic anemia. Chemotherapy, cytoreductive therapy, and monoclonal antibodies are typically used for the treatment of hematological disorders. Stem cell transplantation is also performed for this purpose. However, these conventional therapeutic approaches exhibit several drawbacks, such as nonspecificity and side effects. Aptamers, being RNA or DNA oligonucleotides, selectively bind to a specific complementary molecule and serve as strong therapeutic components, offering significant theranostic implications and numerous therapeutic and diagnostic alternatives for hematological disorders. This article explains the systematic evolution of ligands through exponential enrichment, also known as the SELEX process of aptamer selection, their mechanism of action, and their wide range of applications. Moreover, it discusses the various advanced approaches for aptamer modifications to enhance their flexibility, expanding their applicability. This review article focuses on the recent updates in the application of aptamers in different hematological disorders, highlighting their potential in the therapy and diagnosis of hematological diseases.
2025-11-03 | Evaluation of the novel TMPRSS6 antisense inhibitor sapablursen for treatment of polycythemia vera: Results of the imprssion clinical trial
Abstract Background: Polycythemia vera (PV) is characterized by excessive erythrocytosis and elevated hematocrit (Hct), which is associated with increased risk of thrombotic events. Controlling Hct levels (<45%) is a key therapeutic goal to reduce thrombotic events. Sapablursen (ISIS 702843) is a liver-directed, ligand-conjugated antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6) to enhance hepcidin production thereby restricting iron availability and reduced erythrocytosis. We are reporting the topline results of the IMPRSSION study (NCT05143957), an ongoing global, open-label phase 2 trial evaluating the safety and efficacy of sapablursen for Hct control and reducing phlebotomy rate in patients with PV. Methods: Eligible patients met 2016 WHO diagnostic criteria for PV, were required to have >3 phlebotomies within six months prior to screening, including >1 phlebotomy in the last 12 weeks. There were no exclusions for HCT prior to randomization. Patients received monthly subcutaneous doses of sapablursen in Cohort A (high dose) or Cohort B (low dose), during a 37-week treatment period. The primary efficacy endpoint was the reduction in the frequency of phlebotomy during the last 20 weeks of the treatment period (Week 17-37) compared to baseline (defined as the mean weekly phlebotomy rate during the six months prior to screening through the first dose of sapablursen). Phlebotomy was performed when Hct levels were ≥45% or at the investigator's discretion, confirmation of Hct was not required for phlebotomy. Serial assessments of serum hepcidin, TSAT and ferritin were conducted. The 10-item Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) assessed the change in symptoms from baseline to Week 37. Results: Forty-nine (49) patients received at least one dose of sapablursen (full analysis set) in either Cohort A (n=32) or Cohort B (n=17). The median age was 61 years, 40 (82%) were male, and 29 (59%) classified as high risk. The primary endpoint was met at both dose levels. The weekly phlebotomy rate (mean±SD) decreased from baseline of 0.15±0.07 (~7.8/yr) to 0.05±0.09 (~2.6/yr) during the primary endpoint window (Week 17-37) in Cohort A (n=32, p<0.0001; 95%CI, -0.13, -0.07), and from 0.17±0.07 (~8.9/yr) to 0.07±0.07 (~3.6/yr) in Cohort B (n=17, p=0.0001; 95%CI, -0.14, -0.06). The mean MPN-SAF-TSS was reduced at Week 37 by 32% in Cohort A (change from baseline LSM -6.2, p=0.005) and 11% in Cohort B (change from baseline LSM -2.7, p=0.344). The proportion of patients with Hct control (<45%) without phlebotomy from week 17 to 37 in Cohort A and B was 53% (17/32) and 35% (6/17), respectively. Serum hepcidin was increased from baseline values of 0.25±0.6 to 5.05±4.7 nM at Week 13 in Cohort A (p<0.0001) and from 0.68±1.7 to 2.06±3.6 nM in Cohort B (p=0.0142). A sustained low TSAT was observed between Weeks 17-37 (6.0±2.1% and 5.5±2.0% in Cohort A and 8.9±5.0% and 7.0±3.4% in Cohort B). Serum ferritin increased over time from 18±22 ng/mL and 28±58 ng/mL at baseline in Cohort A and B, respectively, to 44±47 ng/mL and 41±85 ng/mL at Week 37, respectively. Sapablursen was generally safe and well-tolerated. The incidence of injection site reactions was 12.2% (6/49). Injection site reactions did not recur following multiple injections, were not progressive and resolved spontaneously. There was one death on study due to transformation to AML which was deemed as not related to the study drug. Conclusions: Treatment of PV patients with sapablursen increased serum hepcidin, controlled Hct, reduced phlebotomy need and improved quality of life in a dose-dependent manner. These findings highlight the potential of sapablursen as a therapeutic approach in PV and support further development.
2024-01-22 | Idiopathic erythrocytosis: a germline disease?
Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, < 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.
2022-10-25 | The accumulation of miR-125b-5p is indispensable for efficient erythroblast enucleation.
Erythroblast enucleation is a precisely regulated but not clearly understood process. Polycythemia shows pathological erythroblast enucleation, and we discovered a low miR-125b-5p level in terminal erythroblasts of patients with polycythemia vera (PV) compared to those of healthy controls. Exogenous upregulation of miR-125b-5p levels restored the enucleation rate to normal levels. Direct downregulation of miR-125b-5p in mouse erythroblasts simulated the enucleation issue found in patients with PV, and miR-125b-5p accumulation was found in enucleating erythroblasts, collectively suggesting the importance of miR-125b-5p accumulation for erythroblast enucleation. To elucidate the role of miR-125b-5p in enucleation, gain- and loss-of-function studies were performed. Overexpression of miR-125b-5p improved the enucleation of erythroleukemia cells and primary erythroblasts. Infused erythroblasts with higher levels of miR-125b-5p also exhibited accelerated enucleation. In contrast, miR-125b-5p inhibitors significantly suppressed erythrocyte enucleation. Intracellular imaging revealed that in addition to cytoskeletal assembly and nuclear condensation, miR-125b-5p overexpression resulted in mitochondrial reduction and depolarization. Real-time PCR, western blot analysis, luciferase reporter assays, small molecule inhibitor supplementation and gene rescue assays revealed that Bcl-2, as a direct target of miR-125b-5p, was one of the key mediators of miR-125b-5p during enucleation. Following suppression of Bcl-2, the activation of caspase-3 and subsequent activation of ROCK-1 resulted in cytoskeletal rearrangement and enucleation. In conclusion, this study is the first to reveal the pivotal role of miR-125b-5p in erythroblast enucleation.
2021-10-26 | CRISPR/Cas9 mediated CXCL4 knockout in human iPS cells of polycythemia vera patient with JAK2 V617F mutation.
The chemokine CXCL4/platelet factor 4 (PF4) gene, a key player in myelofibrosis, was knocked out by CRISPR/Cas9 in induced pluripotent stem cells (iPS cells) of a polycythemia vera (PV) patient with JAK2 V617F mutation. Two CXCL4KO iPS cell lines with and without JAK2 V617F mutation (UKAi002-B-1 and UKAi002-A-1, respectively) were generated. CXCL4KO iPS cells showed deletion of exon 1 and complete loss of CXCL4 protein. Pluripotency of iPS cells was confirmed by expression of pluripotency markers and trilineage differentiation. CXCL4KO iPS cells are expected to provide a valuable tool for investigating the role of CXCL4 in human diseases.
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Drug Discovery Landscape
23 orphan drug designations for Polycythemia vera, including 3 approved therapies.
23 orphan drug designations for Polycythemia vera, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant fully human IgG1 monoclonal antibody | antibodies | FDA | 2026-01-22 | — | mAbTree Biologics AG |
synthetic 19-mer peptide nucleic acid oligomer consisting of two guanine bases possessing a 5-aminopentyl modification, four adenine bases with a 6-aminohexyl moiety, and a fluorenylethoxycarbonyl (Fethoc) group at the 5' terminal end of the sequence | oligonucleotides | FDA | 2025-08-26 | — | Vanda Pharmaceuticals Inc. |
synthetic 2-O-methoxyethyl phosphorothioate oligoribonucleotide sodium salt consisting of 19 nucleotide residues with the sequence 5'-AMeUAGMeUMeUMeCAMeUAAMeUMeCMeUGGAGA-3' | oligonucleotides | FDA | 2024-12-19 | — | Vanda Pharmaceuticals Inc |
Divesiran | RNAs | EMA | 2024-12-13 | — | Silence Therapeutics GmbH |
Sapablursen | oligonucleotides | FDA | 2024-08-05 | — | Deciphera Pharmaceuticals, LLC |
recombinant humanized monoclonal antibody targeting transmembrane serine protease matripase-6 | antibodies | FDA | 2024-02-08 | — | Disc Medicine, Inc. |
Synthetic double-stranded siRNA oligonucleotide directed against TMPRSS6 mRNA and covalently linked to a ligand containing 3 N-acetylgalactosamine residues | RNAs | FDA | 2022-02-24 | — | Silence Therapeutics plc |
1-(3-methylbutanoyl)-l-aspartyl-l-threonyl-l-histidyl-l-phenylalanyl-l-prolyl-(l-cystinyl-l-isoleucyl-[(n6-(s)-4-carboxy-4-palmitamidobutanoyl)-l-lysinyl]-l-phenylalanyl-l-glutamyl-l-prolyl-l-arginyl-l-serinyl-l-lysinyl-l-glycinyl-l-cystinyl)-l-lysinamide, disulfide, acetate | small molecules | EMA | 2020-10-19 | — | Takeda Pharmaceuticals International AG Ireland Branch |
rusfertide | peptides | FDA | 2020-06-12 | — | Takeda Development Center Americas, Inc. |
idasanutlin | small molecules | FDA | 2017-11-29 | — | Hoffmann-La Roche Inc. |
Givinostat | small molecules | FDA | 2017-09-28 | — | Italfarmaco SpA |
Ruxolitinib phosphate [Jakavi] | small molecules | EMA | 2014-02-19 | — | Novartis Europharm Limited |
Fedratinib | small molecules | FDA | 2013-03-21 | — | Impact Biomedicines |
ropeginterferon alfa-2b-njft [Besremi] | proteins | FDA | 2012-04-02 | 2021-11-12 | PharmaEssentia |
Chimeric locked nucleic acid-deoxynucleoside phosphorothioate-linked oligonucleotide directed against microRNA-451 | oligonucleotides | EMA | 2012-01-11 | — | [INACTIVE] Viridian Therapeutics Europe Limited |
Ropeginterferon alfa-2b [Besremi] | proteins | EMA | 2011-12-09 | — | [INACTIVE] Aop Orphan Pharmaceuticals GmbH |
inhibitor of microRNA-451 | RNAs | FDA | 2011-02-04 | — | miRagen Therapeutics, Inc. |
ruxolitinib [Jakafi XR] | small molecules | FDA | 2010-03-26 | 2026-05-01 | Incyte Corporation |
ruxolitinib [Jakafi] | small molecules | FDA | 2010-03-26 | 2014-12-04 | Incyte Corporation |
Givinostat | small molecules | EMA | 2010-02-03 | — | Italfarmaco S.p.A. |
Acetylsalicylic acid | small molecules | EMA | 2004-07-29 | — | Bayer AG |
natural human lymphoblastoid interferon-alpha | proteins | FDA | 2002-11-18 | — | Amarillo Biosciences, Inc. |
Anagrelide | small molecules | FDA | 1985-06-11 | — | Roberts Pharmaceutical Corp. |
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