RARE DISEASE
Essential thrombocythemia
Essential thrombocythemia
Essential thrombocythemia
Synonyms: ET, Essential thrombocytosis
Synonyms: ET, Essential thrombocytosis
Synonyms: ET, Essential thrombocytosis
Drug discovery
11
drugs
With orphan designations
Overview
Essential Thrombocythemia (ET) is a Philadelphia-negative myeloproliferative neoplasm characterized by sustained thrombocytosis (>450,000/mcL), thrombotic/hemorrhagic complications, and constitutional symptoms. Diagnosis requires exclusion of reactive causes and other MPNs, with mutations in JAK2 (50%), CALR (23.5%), or MPL (5%) supporting clonal origin [1][6][15]. Management focuses on thrombosis prevention, with disease progression risks including myelofibrosis (13%) and acute leukemia (<2%) [1][6][12].
Therapies
Low-risk: Low-dose aspirin (81–100 mg/day) for microvascular symptoms/thrombosis prevention [3][16][19]
High-risk: Cytoreduction (hydroxyurea, pegylated interferon-α) ± aspirin; anagrelide/ruxolitinib for refractory cases [3][5][13]
Cardiovascular risk factor optimization (e.g., hypertension, diabetes control) [1][8][16]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,698 drug discovery papers about Essential thrombocythemia, with 2 first-in-class and 32 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,698 drug discovery papers about Essential thrombocythemia, with 2 first-in-class and 32 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | Pediatric Essential Thrombocythemia With a Novel CALR Mutation: A Case Report.
Pediatric essential thrombocythemia (ET) is extremely rare and frequently lacks identifiable driver mutations. We report a case of a 5-year-old male with ET harboring a novel CALR exon 9 frameshift mutation complicated by acquired von Willebrand syndrome. The patient presented with purpura, extreme thrombocytosis (1900 × 109 /L), and reduced von Willebrand factor activity. Antiplatelet therapy was avoided because of bleeding risk, and anagrelide was initiated. Treatment was associated with reduction in platelet count and improvement in von Willebrand factor activity. This case expands the molecular spectrum of pediatric CALR-mutated ET and highlights the importance of individualized management in children with extreme thrombocytosis. The authors have confirmed clinical trial registration is not needed for this submission.
2026-09-28 | CALR-mutated myeloproliferative neoplasms: Refining molecular risk beyond the driver.
Calreticulin (CALR)-mutated myeloproliferative neoplasms (MPNs) are generally associated with favourable outcomes, yet considerable heterogeneity persists across the disease course. Mawalkar et al. provide long-term data across essential thrombocythaemia (ET), post-ET myelofibrosis (MF) and primary MF, highlighting the prognostic relevance of additional somatic mutations. The contribution of co-mutational context, variant allele frequency (VAF), disease origin and timing of molecular assessment remains incompletely defined. Commentary on: Mawalkar et al. Outcome heterogeneity in CALR-mutated myeloproliferative neoplasms. Br J Haematol 2026 (Online ahead of print). doi: 10.1111/bjh.70859.
2026-09-26 | The Roles of Genetic and Epigenetic Abnormalities in Essential Thrombocythemia.
Essential thrombocythemia (ET) is a Ph(-) myeloproliferative neoplasm characterized by elevated platelet counts. Patients most often have one of the three following driver mutations: JAK2, MPL, or CALR. However, these mutations are not detected in approximately 10-15% of patients, who are thus referred to as "triple-negative" (TN). Background/Objectives: In recent years, there have been breakthroughs in the genetic diagnosis of hematological diseases and progress in understanding their epigenetic basis. Aim: This study aimed to review the available literature and systematize the current knowledge on the molecular abnormalities in essential thrombocythemia. Particular attention was paid to the impacts of genetic mutations and epigenetic changes-such as abnormalities in non-coding RNA expression, DNA methylation, and histone modifications-on disease development and their clinical significance in patients with essential thrombocythemia. The most important publications on genetic and epigenetic mechanisms in essential thrombocythemia were reviewed and summarized. Methods: A review of the available literature was conducted using selected online databases. Publications from 2003 to 2026 were considered, covering the diagnosis and classification criteria for essential thrombocythemia, its genetic and epigenetic basis, and the associated impacts on the disease course. Conclusions: Although understanding the precise roles of genetic and epigenetic abnormalities in essential thrombocythemia remains challenging, they offer many opportunities for use as new diagnostic biomarkers and for the development of novel targeted treatment options. Further research is needed to better understand the genetic and epigenetic changes occurring in ET.
2026-09-18 | Molecular Response, Event-Free Survival, and Treatment-Free Remission in Myeloproliferative Neoplasms: Update and Review with Insights from MPN Asia 2026.
Therapeutic goals in BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are evolving to include biologically anchored measures of disease modification with control of blood counts, splenomegaly, and symptoms. Disease modification endpoints and their linkage to survival in MPNs were central to the framework of MPN Asia 2026, which took place in Seoul. This review summarizes key themes from MPN Asia 2026 and relevant recent literature, examining the evolving roles of molecular response and long-term clinical benefits within a broader disease-modification framework across polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Clinical trials with ropeginterferon alfa-2b were central to the discussions given these studies have contributed to the evolving paradigm of disease modification in MPNs, underscoring the importance of molecular response and event-free survival (EFS) in MPN management. In PV, ropeginterferon alfa-2b treatment provides a clinical model linking durable hematologic control and deep JAK2V617F variant allele frequency (VAF) reduction with improved long-term outcomes such as EFS, and prospective treatment-discontinuation strategies. Data from Europe and Asia supports the importance of early disease control, adequate interferon exposure, and longitudinal molecular monitoring. In ET, randomized data with ropeginterferon alfa-2b and emerging new treatment approaches such as lysine-specific demethylase 1 inhibition and mutant CALR-directed therapy are incorporating molecular endpoints into clinical development. However, the association between VAF reduction and thrombosis prevention, disease modification, EFS, and treatment-free remission (TFR) need to be elucidated. In MF, molecular profiling is already integral to prognostication and treatment selection, and disease modification assessment will likely require endpoints encompassing more than symptoms and spleen response, such as anemia response, bone marrow fibrosis change, clonal evolution, patient-reported outcomes, and importantly progression-free and overall survival. Molecular response, clonal suppression, prevention of vascular and progression events, survival outcomes such as EFS and TFR play increasingly important roles in MPN management.
2026-09-06 | Atypical Presentation of a Splenic Abscess Secondary to Splenic Artery Thrombosis With Isolated Confusion: A Case Report.
Splenic abscess is a rare but life-threatening condition whose diagnosis is frequently delayed because of its nonspecific presentation. Development of a splenic abscess following splenic infarction secondary to splenic artery thrombosis is exceptional, particularly when revealing an underlying myeloproliferative neoplasm. An 85-year-old woman presented to the emergency department after three weeks of intermittent confusion without fever, abdominal pain, or gastrointestinal symptoms. While neurological investigations were unrevealing, thoracoabdominal computed tomography unexpectedly demonstrated a large splenic abscess associated with splenic artery thrombosis and bilateral pulmonary emboli. Laboratory tests showed marked systemic inflammation and severe thrombocytosis. Ultrasound-guided percutaneous drainage isolated Escherichia coli, and treatment with intravenous antibiotics and therapeutic anticoagulation was initiated. The patient's course was complicated by septic shock requiring intensive care admission but ultimately evolved favorably with prolonged antimicrobial therapy and continuous percutaneous drainage, avoiding splenectomy. Additional investigations identified deep vein thrombosis and confirmed JAK2 V617F-positive essential thrombocythemia as the cause of a systemic prothrombotic state leading to multiple arterial and venous thrombotic events. This case illustrates how splenic abscess may present solely as delirium in older adults, without localizing abdominal symptoms. Emergency physicians should consider occult intra-abdominal infection in elderly patients presenting with unexplained delirium and inflammatory syndrome. When unusual arterial and venous thromboses coexist, an underlying myeloproliferative disorder should be actively investigated. In selected patients, image-guided percutaneous drainage combined with prolonged antibiotic therapy may provide an effective spleen-preserving alternative to splenectomy.
cell therapies
2025-11-21 | Sabotaged Integral HSC Heterogeneity Underlies Essential Thrombocythemia Development.
Essential thrombocythemia (ET) includes the JAK2 -, CALR-, and MPL-mutated subtypes, and a triple-negative (TN) ET subtype, which lacks these canonical drivers. How specific driver mutations affect hematopoietic stem cell (HSC) heterogeneity and their relation to ET pathogenesis remain unclear. Here, by using single-cell RNA sequencing (scRNA-seq) combined with driver mutation detection across ET patients, it is found that MPL-mutated HSCs exhibited aberrant metabolism, CALR-mutated HSCs displayed active cell cycling, while JAK2 V617F-mutated HSCs demonstrated enhanced megakaryocyte (Mk) priming capacity and interferon (IFN) response. An HSC subset is identified in TN ET that transcriptionally resembled driver-mutated HSCs, exhibiting enhanced megakaryocytic priming and proliferative activity. Notably, the frequency of a CXCR4+ HSC subset is reduced across the ET spectrum. Loss of CXCR4+ HSCs skewed lineage differentiation of HSCs toward the myeloid lineage, whereas restoring this subset delayed the onset of ET. Altogether, this study reveals both the shared and distinct molecular features of mutant HSCs in ET and provides novel insights into the pathogenesis and potential therapeutic strategies of ET.
2024-04-01 | Management of paroxysmal nocturnal hemoglobinuria in CALR mutated post‐essential thrombocythemia myelofibrosis: A case report
Abstract Paroxysmal nocturnal hemoglobinuria (PNH) results from the loss of erythrocyte surface proteins, leading to complement activation and its spectrum of effects. We explore this case of a 57‐year‐old man with post‐essential thrombocythemia (ET) myelofibrosis (MF) who developed symptomatic anemia with evidence of hemolysis on lab work. While hemolysis was localized to be intramedullary based on workup, the exact diagnosis was undetermined, leading to a prolonged course of steroid therapy to control anemia. The hemolysis was eventually attributed to PNH diagnosed on flow cytometry and the patient was treated with complement inhibitors with eventual failure of therapy. He ultimately underwent a successful hematopoietic cell transplant (HCT) with post‐transplantation flow cytometry showing complete resolution of PNH. While PNH has been identified as a progression of myelodysplastic syndromes, the mechanisms of its rare development in myeloproliferative neoplasms are poorly elucidated. Furthermore, its rarity and often vague symptoms make diagnosis and treatment a challenge. This is the second reported case of a JAK2‐negative, CALR‐positive post‐ET MF and the first reported case to be treated with HCT. This case probes for further insight into the clinical significance between MF and PNH, its impact on management, and further consideration for HCT as curative therapy in such patients who fail complement inhibitor therapy.
2023-10-30 | The effect of thrombocytapheresis on hemogram and biochemistry parameters in patients with essential thrombocytemia.
Essential thrombocythemia is one of the chronic myeloproliferative neoplasms characterized by clonal proliferation of myeloid cells with variable morphological maturation and hematopoietic activity.It is characterized by excessive clonal platelet production with a tendency to thrombosis and bleeding. Thrombocytapheresıs is the removal of platelets by apheresis techniques. Thrombocytapheresıs is generally recommended in patients with essential thrombocythemia with acute, severe thrombotic or hemorrhagic events. The study included 39 patients who were diagnosed with essential thrombocythemia, started cytoreductive and aspirin therapy, and underwent thrombocytapheresıs due to the development of acute severe thrombotic or hemorrhagic events, diagnosed in the adult hematology clinic of İnönü University Turgut Ozal Medical Center. Hemogram and biochemistry values of the patients were scanned retrospectively. After thrombocytapheresıs, a statistically significant difference was found between the first and last measurements of hemoglobin, mean platelet volume, White blood cell, neutrophil, platelet, platelet distribution width, creatine, lactate dehydrogenase, fibronogen and calcium levels of the patients. The use of thrombocytapheresıs in patients with essential thrombocytosis causes a rapid decrease in platelet values as well as an effect on hemogram and biochemistry parameters. Other hemogram and biochemistry parameters such as platelet value should be monitored in patients.
2023-01-20 | [Durable remission following donor lymphocyte infusion for post-transplant relapse of acute myeloid leukemia developing from secondary myelofibrosis].
Essential thrombocythemia gradually developed into secondary myelofibrosis and progressed to leukemia eight months later in a 53-year-old man. After remission induction therapy, he achieved remission by undergoing allogeneic hematopoietic stem cell transplantation from unrelated patients in non-remission. However, peripheral blood WT-1 mRNA gradually increased, and the disease relapsed three years and six months after transplantation. He was taking prednisolone (7.5 mg) and tacrolimus (5 mg) for chronic pulmonary graft-versus-host disease (GVHD) and was reluctant to reduce or discontinue immunosuppressive drugs; therefore, donor lymphocyte infusion (DLI) was performed for a total of five times. Four months after the fifth DLI, cutaneous GVHD appeared, a slow decrease in WT-1 mRNA was observed, and blasts in the peripheral blood disappeared. One year and three months after the last DLI, he achieved complete remission. Although DLI for post-transplant relapse in patients with secondary myelofibrosis or leukemia is rare, it can be beneficial for post-relapse therapy.
2022-09-14 | The safety and performance of the Spectra Optia apheresis system platelet depletion protocol in patients with elevated platelet counts
Abstract Background Thrombocytosis is a presenting and progressive clinical feature found in multiple disease states. It is characterized by high platelet (PLT) counts (>450 × 10 9 /L) and can lead to thrombohemorrhagic events. Thrombocytapheresis or platelet depletion (PLTD) can be performed in acutely symptomatic patients suffering from thrombocytosis and may reduce or prevent acute serious complications associated with thrombocythemia thereby enabling patients to receive potentially curative high‐dose chemotherapy. Methods This report details the results from 2 clinical studies, one conducted in the European Union (EU) and one in the People's Republic of China, assessing the PLTD procedure on the Spectra Optia Apheresis System. The primary objective of both studies was to assess the safety and performance of the PLTD procedure in patients with elevated PLT counts. Results Data were collected from 56 participants completing 64 PLTD procedures. The mean percent change in PLT count and collection efficiency (CE1) was 55.1% and 68.5%, respectively. In the EU study, 6 participants experienced a total of 9 adverse events (AEs) and in the China study, 44 participants reported a total of 212 AEs. In both studies, the majority of AEs reported were Grade 2 or lower and no serious AEs, unanticipated adverse device effects, or AEs leading to death were reported. Conclusions The data collected within these studies indicate that the PLTD procedure is well tolerated and effective at reducing circulating PLTs in patients suffering from thrombocytosis as evaluated by a percent decrease in PLT count, CE1, and AE incidence.
proteins
2026-09-17 | Interferon-α vs hydroxyurea in patients with myeloproliferative neoplasms (DALIAH): a multicentre, randomised, open-label, phase 3 trial in Denmark.
Hydroxyurea (HU) is the most commonly used cytoreductive treatment for patients with myeloproliferative neoplasms (MPN), but emerging data on pegylated interferon-alpha2 (pegIFNα) are encouraging. Optimal first-line treatment remains unclear. DALIAH was a randomised, open-label, parallel-group, phase 3 trial conducted at nine centres in Denmark comparing HU with pegIFNα in patients with newly diagnosed MPN. Adults (≥18 years) with newly diagnosed or cytoreductive treatment-naïve MPN (essential thrombocythaemia [ET], polycythaemia vera [PV], prefibrotic myelofibrosis [pre-PMF], or primary myelofibrosis [PMF]; according to 2008 World Health Organization [WHO] criteria) and evidence of active disease were eligible, regardless of risk score. Patients aged >60 years were randomised (1:1:1) to either HU, pegIFNα-2a, or pegIFNα-2b; patients aged ≤60 years were randomised (1:1) to either pegIFNα-2a or pegIFNα-2b. The primary endpoint was the proportion of molecular responders (MR; partial or complete) at 18, 36, and 60 months (intention-to-treat [ITT], HU vs pegIFNα). This trial was registered with ClinicalTrials.gov, NCT01387763. Between Feb 7, 2012, and July 6, 2015, 203 eligible participants were enrolled in the modified ITT population (HU n = 38 [19%], pegIFNα n = 165 [81%]). In the ITT analysis, MR proportions were similar between HU and pegIFNα at 18 months (19% vs 21%, p = 1·00), 36 months (19% vs 26%, p = 0·64), and 60 months (23% vs 24%, p = 1·00). In the per-protocol (PP) analysis, restricted to patients who remained on therapy, pegIFNα showed higher MR beyond 36 months (36 months: 23% vs 56%, p = 0·01; 60 months: 35% vs 67%, p = 0·03). At month 60, PegIFNα discontinuation was high (65% vs 37% HU, p = 0·0019). No significant difference in grade ≥3 adverse events was observed between groups (HU 58% vs pegIFNα 45%, p = 0·21). Adverse events occurring in ≥10% of patients differed between treatments: dyspepsia, pyrexia, and urinary tract infections were more common with HU, whereas fatigue, influenza-like illness, injection-site irritation, myalgia, and decreased white cell blood count were more frequent with pegIFNα. Anaemia and decreased neutrophil count were the most common haematological events in both groups. Treatment-related adverse events were reported in 77 patients (HU 27% vs pegIFNα 41%, p = 0·14) and led to permanent discontinuation in 13 patients (all pegIFNα). HU and pegIFNα display distinct response kinetics. Molecular response was similar in the ITT analysis, reflecting that non-response largely resulted from higher pegIFNα discontinuation rather than lack of efficacy. Among patients who tolerated therapy, pegIFNα achieved superior long-term molecular responses. Findings should be considered within the context of the significantly higher treatment discontinuation rate with pegIFNα than with HU. These findings suggest that pegIFNα may offer long-term molecular benefit in selected patients highlighting the need for biomarkers that predict response and long-term tolerability, preferably already at diagnosis. OUH-Region Sjaelland Faelles Forskningspulje, Region Sjællands Sundhedsvidenskabelige Forskningsfond (RSSF) 2018, Gangstedfonden, OUH Frie Forskningsmidler, Swedish Orphan, Fonden til Lægevidenskabens Fremme, Ellen og Aage Fausboells Helsefond af 1975, and Desirée og Niels Ydes Fond.
2026-08-26 | Pregnancy Transiently Normalized Platelet Counts in Essential Thrombocytosis.
Outcomes of pregnancies complicated by essential thrombocytosis (ET) are worse than those of normal pregnancies. Aspirin, heparin, and interferon (IFN)-α are well-tolerated during pregnancy and prescribed in accordance with the risk of thrombosis. However, some evidence suggests that platelet count decreases during ET-complicated pregnancies. We retrospectively analyzed changes in platelet count in ET-complicated pregnancies. Platelet count decreased during pregnancy without IFN-α use, and 83% of pregnant women had a platelet count of ≤450×109/L. Furthermore, all pregnant women achieved a platelet count of ≤600×109/L. One the basis of revised IPSET-thrombosis score, risk was classified as low or very low. Aspirin use starting in early pregnancy was associated with a higher rate of successful delivery, even in patients with prior miscarriage. These findings suggest that platelet counts decrease in selected low-risk and very-low-risk ET-complicated pregnancies and that cytoreductive therapy with IFN-α may be avoidable in some cases. These results should be interpreted cautiously because of the small sample size and retrospective study design.
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.
2026-06-17 | Ropeginterferon alfa-2b-njft treatment in essential thrombocythemia across different driver mutations: results from a North American, single-arm, multicentre study (EXCEED-ET).
Ropeginterferon alfa-2b-njft (ropeg), a mono-PEGylated interferon-α, showed efficacy and safety in patients with hydroxyurea-intolerant/resistant essential thrombocythemia (ET) in the phase 3 SURPASS-ET largely conducted in Asia. Here we report the results from the EXCEED-ET study, which evaluated ropeg in both treatment-naïve and hydroxyurea pre-treated ET in North America. The single-arm, multicentre, phase 2b trial EXCEED-ET was conducted at 28 centers in the United States and Canada. Patients with ET enrolled were required to have a platelet count >450 × 109/L at screening. Patients were eligible regardless of prior cytoreductive therapy status and included both treatment-naïve and hydroxyurea-pretreated patients. Ropeg was subcutaneously administered in an accelerated titration schedule at 250 μg at Week 0, 350 μg at Week 2, and 500 μg from Week 4 and beyond. The primary endpoint was durable, modified European LeukemiaNet (ELN) response at both Months 10 and 13 (ClinicalTrials.gov identifier: NCT05482971). Between January 17, 2023, and May 15, 2025, 106 patients were screened and 91 were enrolled. At baseline, participant median age was 57 years (range, 22-84) with 57/91 (62.6%) being female and 71/91 (78.0%) being White. Among 91 patients enrolled, durable modified ELN response rate was 60.2% (95% CI, 49.0-71.4). The median time to hematologic response was only 8.4 weeks (95% CI: 8.1-11.9). Splenomegaly and symptom improvement or non progression occurred in 90/91 (98.9%) and 71/91 (78.0%), respectively. Seven of 91 (7.7%) patients with palpable spleen at baseline and all had an improvement in disease-related signs. The rates of molecular response for driver mutations at Month 13 as defined by ELN2009 criteria were 35.0% (7/20) for patients with JAK2V617F, 16.0% (4/25) for CALR, and 25.0% (2/8) for MPL mutations. One (1/1) TP53 mutation-positive patient showed a complete molecular response. Thrombosis and progression occurred in 3.4% (3/91) and 1.1% (1/91), respectively. Most treatment-emergent adverse events were mild, including fatigue (60%) and reversible transaminase elevations (58%). There was no grade 5 TEAE and one (1.1%) grade 4 TEAE (hepatitis toxic) which recovered without sequelae. Grade ≥3 TEAEs occurred in 27.5% (25/91) of the participants, most commonly with alanine aminotransferase and aspartate aminotransferase increases (4.4%; 4/91), neutrophil count decrease (4.4%; 4/91), fatigue (3.3%; 3/91) and lymphocyte count decrease (3.3%; 3/91). Treatment-related serious adverse events occurred in 5.5% (5/91) of patients. Pneumonia was the most common SAE, occurring in 2/91 (2.2%) patients. Ropeg-related discontinuations occurred in 9/91 (9.9%) patients. Ropeg showed efficacy and substantial molecular responses with good overall tolerability across a broad ET population. PharmaEssentia.
2026-04-17 | Essential Thrombocythemia-Associated Distal Radial Pseudoaneurysm Treated With Thrombin Injection.
Distal radial artery access is associated with a low complication rate and infrequently leads to pseudoaneurysm formation. Consequently, the clinical characteristics of pseudoaneurysms in essential thrombocythemia (ET) are not well characterized. A 79-year-old woman with ET developed a pulsatile wrist mass 2 weeks after coronary angiography via distal radial artery access. Imaging revealed a 17-mm pseudoaneurysm. Conservative compression was unsuccessful. The initial thrombin injection resulted in partial thrombosis with distal escape and re-entry flow. A subsequent injection with manual proximal radial compression achieved complete thrombosis without complications. In ET, qualitative platelet dysfunction may compromise thrombus stability after thrombin injection. Proximal radial compression is crucial in distal radial pseudoaneurysms to prevent distal escape and achieve durable thrombosis. Because ET can compromise thrombus stability, sufficient inflow reduction is essential for successful thrombin injection in distal radial pseudoaneurysms.
antibodies
2026-08-19 | Immunotherapeutic targeting of calreticulin mutant myeloproliferative neoplasms.
Calreticulin (CALR) frameshift mutations drive the majority of JAK2/MPL-wild-type cases of essential thrombocythemia and myelofibrosis, producing a shared novel C-terminus that activates the thrombopoietin receptor and leads to constitutive Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. CALR mutations transform the multifunctional endoplasmic reticulum (ER)-resident protein into an oncogenic driver that aberrantly traffics to the cell surface, activates the thrombopoietin receptor, MPL, and promotes MF megakaryocytic proliferation and hemopoietic stem cell fitness. Clinically, CALR-mutated MPNs affect younger patients, exhibit thrombocytosis and progressive anemia, and, in MF patients, are associated with a superior survival compared with JAK2- or MPL-mutated disease, yet responses to hydroxyurea and ruxolitinib remain inferior. The C-terminal motif shared between CALR mutations is presented extracellularly on major histocompatibility complex (MHC) Class I molecules and in complex with the thrombopoietin receptor enabling targeting with vaccination and antibody based therapeutic platforms, respectively. Mutant CALR peptide vaccines induce T cell responses but have failed to result in hematologic or molecular responses. Mutant CALR-specific monoclonal antibodies, such as Fc-silent antagonists, can block mutant-CALR-MPL signaling, suppress hematopoietic stem and progenitor cells (HSPC) proliferation and megakaryopoiesis, and achieve rapid, durable hematologic remissions with minimal toxicity in early-phase trials. Preclinical antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor T cell (CAR-T) cells also show potent, selective mutant-cell killing. Here we review the basis and ongoing translational and clinical efforts in the development of CALR-targeted immunotherapies that offer a potential shift from symptom management to disease-modifying treatment in this molecularly defined MPN subset.
2026-04-20 | From JAK to CALR: redefining therapeutic targets in myeloproliferative neoplasms.
This review highlights the emergence of CALR as a promising therapeutic target in CALR-mutated myeloproliferative neoplasms. While current JAK inhibitors alleviate symptoms and reduce thrombosis risk, they lack clonal specificity, have a limited impact on the natural history of disease, and are limited by toxicity and resistance. In contrast, CALR mutations generate a unique, disease-specific neoepitope that drives disease pathogenesis through aberrant MPL activation and is accessible on the cell surface, making it an ideal immunologic and antibody target. Preclinical and early clinical advances - including monoclonal antibodies, bispecific T-cell engagers, CAR-T therapies, antibody-drug conjugates, and peptide/viral vector vaccines - have demonstrated selective activity against CALR-mutant clones while sparing normal hematopoiesis, with encouraging evidence of molecular remissions and disease modification. Although challenges such as immune tolerance remain, mutant CALR-directed therapies represent a potential transformative shift in essential thrombocythemia, and primary myelofibrosis treatment.
2025-08-26 | Novel strategies targeting mutant calreticulin in essential thrombocythemia and myelofibrosis.
The discovery of calreticulin (CALR) mutations in patients with myeloproliferative neoplasms (MPNs) has paved the way for the elucidation of a unique disease mechanism that is particularly well suited to targeting by biologics. All MPN-associated pathogenic CALR mutations are characterized by a frameshift, resulting in translation of the same neoantigen peptide. This neoantigen directly activates the thrombopoietin receptor, leading to uncontrolled neoplastic cell proliferation. Current therapeutic approaches for MPNs are focused primarily on blood count control. Furthermore, current approaches are neither disease modifying nor clonally selective. However, because the mutant CALR neoantigen peptide is functional and not expressed in normal physiology, it is an ideal drug target. Here, we review the structure and function of mutant CALR, including the subtle yet clinically and therapeutically relevant differences between the 2 most commonly occurring types of mutation. We also review the current therapeutic landscape for CALR-mutated MPNs, highlighting the areas in which current approaches are inadequate. Finally, we review ongoing clinical and preclinical experimental approaches for targeting mutant CALR in MPNs in a clonally selective manner using monoclonal antibodies, bispecific antibodies, cancer vaccination, chimeric antigen receptor T cells, and antibody-drug conjugates. Taken together, we expect that ongoing developments in mutant CALR-targeted therapeutics will lead to promising novel strategies for long-term disease control.
2025-03-29 | Tailored Treatments: Utilizing Anti-TNFs for Ankylosing Spondylitis and Essential Thrombocytosis
Thrombocytosis is a condition that is often detected incidentally and can be seen both in the course of myeloproliferative diseases (MPD) and as a reactive condition. Ankylosing spondylitis (AS) is a chronic multisystemic inflammatory disease that mainly affects the spine. Mild to moderate thrombocytosis may occur secondary to the course of AS. In the treatment of AS, tumor necrosis factor inhibitor (anti-TNF) treatments are actively used as first-line therapy. The number of cases of MPDs occurring in the course of AS reported in the literature is limited. Although the exact effect of anti-TNF treatment on the MPD process is not fully known, there are publications stating that caution should be exercised in cases of MPD. By this case, we wanted to share our experience of using anti-TNF therapy in a patient diagnosed with ET in the course of AS. The 35-year-old male patient had been diagnosed with AS for 11 years and had been followed up by hematology with the diagnosis of essential thrombocytosis (ET) since 2010. When there was no response to indomethacin and sulfasalazine treatments, the patient was first given etanercept, and after secondary unresponsiveness, infliximab and adalimumab treatments were given. Despite the use of multiple anti-TNFs, no hematological deterioration was detected in terms of ET. Clinical and laboratory responses were also obtained in terms of AS. The patient has been stable and in remission in terms of both AS and ET since 2016.
2025-02-17 | CALR-mutated myeloproliferative neoplasms.
Calreticulin (CALR) is a chaperone protein that plays a crucial role in protein folding quality control and calcium homeostasis. Mutations in CALR result in a mutated protein lacking key calcium-binding sites and the KDEL sequence, leading to a constitutive activation of the MPL-JAK2-STAT5 pathway, which is involved in the pathogenesis of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Despite advancements in understanding the role of CALR mutations, current therapeutic strategies remain focused on managing symptoms and complications, with allogeneic stem cell transplantation (alloHSCT) as the only curative option. Emerging research is exploring novel immunotherapeutic approaches targeting mutant CALR, including the development of anti-CALR antibodies and T-cell receptor-mediated therapies, offering potential new avenues for treatment in CALR-mutated MPNs. In this review, we will discuss on the role of CALR in MPNs, focusing on its biological structure and its implications on the prognosis and treatment of essential thrombocythemia and primary myelofibrosis.
other
2026-01-14 | Polycythemia Vera and Essential Thrombocythemia: A Nationwide Population-Based Study on Treatment Patterns, Vascular Complications and Survival.
Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with a well-recognized increased risk of thrombotic events, bleeding, and all-cause mortality, but the frequency of these outcomes during treatment has rarely been assessed in large cohorts. In this nationwide, population-based study, we analyzed 2604 PV and 3141 ET patients using multiple Swedish health care registers, covering 43 612 patient-years. Rates of arterial and venous events, major bleeding, and all-cause mortality (ACM) were evaluated across therapies. Unexpectedly, 42.3% of low-risk PV patients and 29.7% of very low/low-risk ET patients received hydroxyurea (HU) during follow-up. High-risk PV patients treated with interferon (IFN) exhibited the lowest arterial event rate (2.21 per 100 patient-years). In high-risk ET, patients with IFN therapy experienced the lowest arterial and venous event rates (1.55 and 0.44 per 100 patient-years). Advanced age and leukocytosis at diagnosis independently predicted thrombosis, bleeding, and ACM in both PV and ET. Multivariable analysis showed that HU and IFN were associated with reduced ACM risk; HU also conferred protection against thromboembolism and major bleeding. This study highlights risk factors associated with complications during treatment in a real-world context and reinforces the role of HU and IFN as first-line therapies in PV and ET.
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.
2025-03-21 | Imetelstat in myeloid malignancies: current data and future directions.
Telomerase reactivation allows cancer cells to maintain telomere length and evade senescence, making it an appealing therapeutic target. Imetelstat, an antisense oligonucleotide, is the first clinically effective telomerase inhibitor approved by the FDA and the European Commission for treating anemia in transfusion-dependent low-risk myelodysplastic syndromes (MDS). Sources for this review were identified through searches of PubMed, ClinicalTrials.gov, and conference abstracts. This review highlights the pharmacology, efficacy, and ongoing trials of imetelstat in treating MDS, myelofibrosis, essential thrombocythemia, and other malignancies. In the IMerge trial, imetelstat induced durable transfusion independence in heavily transfused LR-MDS patients. Pilot trials in myelofibrosis suggest imetelstat's potential disease-modifying properties and survival benefit, warranting further studies of imetelstat as a monotherapy or in combination therapies. Imetelstat can cause thrombocytopenia, leukopenia, elevated liver enzymes, and infusion reactions, which are mostly reversible but may rarely lead to fatal events. Future clinical trials in LR-MDS should focus on optimal sequencing and combination strategies for imetelstat with other agents, and identifying biomarkers that can predict response. Monitoring real-world outcomes will offer valuable insights into imetelstat's safety and efficacy in patient populations underrepresented in clinical trials. Imetelstat's role in other malignancies, especially myelofibrosis, is being explored.
2024-06-04 | Decreasing circ_0014614 promotes the differentiation of bone marrow flineage cells into megakaryocytes in essential thrombocythemia via activiation of miR-138-5p/caspase3 axis.
Circular RNAs (circRNA) are pivotal in hematological diseases. Previous study showed that circ_0014614 (circDAP3) was significantly underexpressed in bone marrow-derived exosomes from essential thrombocythemia (ET) patients, affecting the differentiation of bone marrow lineage cells into megakaryocytes. Fluorescence in situ hybridization (FISH) was used to display circ_0014614's primary cytoplasmic location in K562 cells. Cytoscape software was used to predict the circRNA-miRNA-mRNA networks, and their expression at the cellular level was detected by Quantitative reverse transcription-polymerase chain reaction (qRT-PCR). qRT-PCR was utilized to detect the expression levels of circ_0014614，miR-138-5p and caspase3 mRNA. Western blot was used to determine the protein levels of GATA-1, RUNX-1, NF-E2, CD41 and caspase3. The proliferation of K562 cells was assessed using the Cell Counting Kit-8 (CCK-8) Assay. Furthermore, the interplay between miR-138-5p and circ_0014614 or caspase3 was elucidated through a Dual-luciferase reporter assay. FISH assay indicated circ_0014614's primary cytoplasmic location in K562 cells. In ET bone marrow and K562 cells, circ_0014614 and caspase3 were down-regulated, whereas miR-138-5p saw a significant surge. Overexpressing circ_0014614 curtailed K562 cells' proliferation and differentiation. Further, circ_0014614 targeted miR-138-5p, with heightened miR-138-5p levels counteracting circ_0014614's inhibition. MiR-138-5p further targeted caspase3, and caspase3 silencing neutralized suppressed miR-138-5p's effects on K562 cell differentiation. Circ_0014614 was down-regulated in ET bone marrow and bone marrow lineage cells, and upregulating circ_0014614 can inhibit bone marrow lineage cells' proliferation and differentiation into megakaryocytes. Mechanistically, circ_0014614 functioned as ceRNA via sponging miR-138-5p and alleviated the inhibitory effect of miR-138-5p on its target caspase3, which potentially deters tumor activity in ET.
2023-10-31 | 1138 TGFβ-specific T cells recognize megakaryocyte progenitors in patients with myeloproliferative neoplasms
Background
Chronic myeloproliferative neoplasms (MPN) are a group of diseases that are characterized by the hyperproliferation of mutated hematopoietic stem cells (HSCs) in the bone marrow. Clinically, they can progress to myelofibrosis and acute myeloid leukemia. Megakaryocytic hyperplasia is known to drive fibrotic progression through the secretion of fibrosis-promoting factors such as transforming growth factor beta (TGFβ). Previous work from our group has demonstrated the existence of proinflammatory TGFβ-specific CD4+ and CD8+ T cells that are able to recognize and react towards cancer cells and autologous myeloid cells in a TGFβ-dependent manner. In this study, we investigated the presence of TGFβ-specific T cells in patients with MPN and examined their ability to target key cell types involved in the disease pathogenesis, including megakaryocyte progenitors.
Methods
T-cell responses towards a TGFβ-derived peptide epitope were assessed in peripheral blood mononuclear cells (PBMCs) from 102 patients with MPN and 34 healthy donors (HDs) using interferon gamma (IFN-γ) ELISPOT and intracellular cytokine staining. TGFβ-specific CD4+ T-cell cultures were generated from several patients with MPN by enrichment of reactive T cells following in vitro stimulation and subsequent rapid expansion. Autologous megakaryocyte progenitors were generated through in vitro differentiation of HSCs and expression of megakaryocytic surface markers was demonstrated using flow cytometry. The functional recognition of autologous megakaryocyte progenitors by TGFβ-specific CD4+ T cells was assessed through co-culturing and subsequent intracellular cytokine staining. The production of TGFβ in megakaryocyte progenitors was quantified using ELISA and western blotting.
Results
We describe the presence of TGFβ-specific CD4+ T cells in patients with MPN. We demonstrate stronger TGFβ-specific T-cell responses in patients with essential thrombocythemia (ET) as compared to both HDs and patients with polycythemia vera (PV) or primary myelofibrosis (PMF). We show that TGFβ-specific T cells initiate a proinflammatory cytokine response upon recognition of autologous megakaryocyte progenitors. We validate that these megakaryocyte progenitors produce significant amounts of TGFβ and express human leukocyte antigen (HLA)-class II on their surface. We are currently investigating the presence of TGFβ-specific T cells in the bone marrow of patients with MPN using T-cell receptor (TCR) sequencing.
Conclusions
Our findings highlight the ability of TGFβ-specific T cells to directly target megakaryocyte progenitors, which is a key cell type contributing to the manifestation and progression of disease in patients with MPN. As such, these results warrant further investigation into TGFβ-based immunomodulatory vaccination in patients with MPN.
Ethics Approval
Patient protocols were approved by the scientific ethics committee for the Capital Region of Denmark. Subjects gave written informed consent to participate in the study before taking part.
small molecules
2026-09-29 | Pediatric Essential Thrombocythemia With a Novel CALR Mutation: A Case Report.
Pediatric essential thrombocythemia (ET) is extremely rare and frequently lacks identifiable driver mutations. We report a case of a 5-year-old male with ET harboring a novel CALR exon 9 frameshift mutation complicated by acquired von Willebrand syndrome. The patient presented with purpura, extreme thrombocytosis (1900 × 109 /L), and reduced von Willebrand factor activity. Antiplatelet therapy was avoided because of bleeding risk, and anagrelide was initiated. Treatment was associated with reduction in platelet count and improvement in von Willebrand factor activity. This case expands the molecular spectrum of pediatric CALR-mutated ET and highlights the importance of individualized management in children with extreme thrombocytosis. The authors have confirmed clinical trial registration is not needed for this submission.
2026-09-28 | CALR-mutated myeloproliferative neoplasms: Refining molecular risk beyond the driver.
Calreticulin (CALR)-mutated myeloproliferative neoplasms (MPNs) are generally associated with favourable outcomes, yet considerable heterogeneity persists across the disease course. Mawalkar et al. provide long-term data across essential thrombocythaemia (ET), post-ET myelofibrosis (MF) and primary MF, highlighting the prognostic relevance of additional somatic mutations. The contribution of co-mutational context, variant allele frequency (VAF), disease origin and timing of molecular assessment remains incompletely defined. Commentary on: Mawalkar et al. Outcome heterogeneity in CALR-mutated myeloproliferative neoplasms. Br J Haematol 2026 (Online ahead of print). doi: 10.1111/bjh.70859.
2026-09-26 | The Roles of Genetic and Epigenetic Abnormalities in Essential Thrombocythemia.
Essential thrombocythemia (ET) is a Ph(-) myeloproliferative neoplasm characterized by elevated platelet counts. Patients most often have one of the three following driver mutations: JAK2, MPL, or CALR. However, these mutations are not detected in approximately 10-15% of patients, who are thus referred to as "triple-negative" (TN). Background/Objectives: In recent years, there have been breakthroughs in the genetic diagnosis of hematological diseases and progress in understanding their epigenetic basis. Aim: This study aimed to review the available literature and systematize the current knowledge on the molecular abnormalities in essential thrombocythemia. Particular attention was paid to the impacts of genetic mutations and epigenetic changes-such as abnormalities in non-coding RNA expression, DNA methylation, and histone modifications-on disease development and their clinical significance in patients with essential thrombocythemia. The most important publications on genetic and epigenetic mechanisms in essential thrombocythemia were reviewed and summarized. Methods: A review of the available literature was conducted using selected online databases. Publications from 2003 to 2026 were considered, covering the diagnosis and classification criteria for essential thrombocythemia, its genetic and epigenetic basis, and the associated impacts on the disease course. Conclusions: Although understanding the precise roles of genetic and epigenetic abnormalities in essential thrombocythemia remains challenging, they offer many opportunities for use as new diagnostic biomarkers and for the development of novel targeted treatment options. Further research is needed to better understand the genetic and epigenetic changes occurring in ET.
2026-09-18 | Molecular Response, Event-Free Survival, and Treatment-Free Remission in Myeloproliferative Neoplasms: Update and Review with Insights from MPN Asia 2026.
Therapeutic goals in BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are evolving to include biologically anchored measures of disease modification with control of blood counts, splenomegaly, and symptoms. Disease modification endpoints and their linkage to survival in MPNs were central to the framework of MPN Asia 2026, which took place in Seoul. This review summarizes key themes from MPN Asia 2026 and relevant recent literature, examining the evolving roles of molecular response and long-term clinical benefits within a broader disease-modification framework across polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Clinical trials with ropeginterferon alfa-2b were central to the discussions given these studies have contributed to the evolving paradigm of disease modification in MPNs, underscoring the importance of molecular response and event-free survival (EFS) in MPN management. In PV, ropeginterferon alfa-2b treatment provides a clinical model linking durable hematologic control and deep JAK2V617F variant allele frequency (VAF) reduction with improved long-term outcomes such as EFS, and prospective treatment-discontinuation strategies. Data from Europe and Asia supports the importance of early disease control, adequate interferon exposure, and longitudinal molecular monitoring. In ET, randomized data with ropeginterferon alfa-2b and emerging new treatment approaches such as lysine-specific demethylase 1 inhibition and mutant CALR-directed therapy are incorporating molecular endpoints into clinical development. However, the association between VAF reduction and thrombosis prevention, disease modification, EFS, and treatment-free remission (TFR) need to be elucidated. In MF, molecular profiling is already integral to prognostication and treatment selection, and disease modification assessment will likely require endpoints encompassing more than symptoms and spleen response, such as anemia response, bone marrow fibrosis change, clonal evolution, patient-reported outcomes, and importantly progression-free and overall survival. Molecular response, clonal suppression, prevention of vascular and progression events, survival outcomes such as EFS and TFR play increasingly important roles in MPN management.
2026-09-06 | Atypical Presentation of a Splenic Abscess Secondary to Splenic Artery Thrombosis With Isolated Confusion: A Case Report.
Splenic abscess is a rare but life-threatening condition whose diagnosis is frequently delayed because of its nonspecific presentation. Development of a splenic abscess following splenic infarction secondary to splenic artery thrombosis is exceptional, particularly when revealing an underlying myeloproliferative neoplasm. An 85-year-old woman presented to the emergency department after three weeks of intermittent confusion without fever, abdominal pain, or gastrointestinal symptoms. While neurological investigations were unrevealing, thoracoabdominal computed tomography unexpectedly demonstrated a large splenic abscess associated with splenic artery thrombosis and bilateral pulmonary emboli. Laboratory tests showed marked systemic inflammation and severe thrombocytosis. Ultrasound-guided percutaneous drainage isolated Escherichia coli, and treatment with intravenous antibiotics and therapeutic anticoagulation was initiated. The patient's course was complicated by septic shock requiring intensive care admission but ultimately evolved favorably with prolonged antimicrobial therapy and continuous percutaneous drainage, avoiding splenectomy. Additional investigations identified deep vein thrombosis and confirmed JAK2 V617F-positive essential thrombocythemia as the cause of a systemic prothrombotic state leading to multiple arterial and venous thrombotic events. This case illustrates how splenic abscess may present solely as delirium in older adults, without localizing abdominal symptoms. Emergency physicians should consider occult intra-abdominal infection in elderly patients presenting with unexplained delirium and inflammatory syndrome. When unusual arterial and venous thromboses coexist, an underlying myeloproliferative disorder should be actively investigated. In selected patients, image-guided percutaneous drainage combined with prolonged antibiotic therapy may provide an effective spleen-preserving alternative to splenectomy.
cell therapies
2025-11-21 | Sabotaged Integral HSC Heterogeneity Underlies Essential Thrombocythemia Development.
Essential thrombocythemia (ET) includes the JAK2 -, CALR-, and MPL-mutated subtypes, and a triple-negative (TN) ET subtype, which lacks these canonical drivers. How specific driver mutations affect hematopoietic stem cell (HSC) heterogeneity and their relation to ET pathogenesis remain unclear. Here, by using single-cell RNA sequencing (scRNA-seq) combined with driver mutation detection across ET patients, it is found that MPL-mutated HSCs exhibited aberrant metabolism, CALR-mutated HSCs displayed active cell cycling, while JAK2 V617F-mutated HSCs demonstrated enhanced megakaryocyte (Mk) priming capacity and interferon (IFN) response. An HSC subset is identified in TN ET that transcriptionally resembled driver-mutated HSCs, exhibiting enhanced megakaryocytic priming and proliferative activity. Notably, the frequency of a CXCR4+ HSC subset is reduced across the ET spectrum. Loss of CXCR4+ HSCs skewed lineage differentiation of HSCs toward the myeloid lineage, whereas restoring this subset delayed the onset of ET. Altogether, this study reveals both the shared and distinct molecular features of mutant HSCs in ET and provides novel insights into the pathogenesis and potential therapeutic strategies of ET.
2024-04-01 | Management of paroxysmal nocturnal hemoglobinuria in CALR mutated post‐essential thrombocythemia myelofibrosis: A case report
Abstract Paroxysmal nocturnal hemoglobinuria (PNH) results from the loss of erythrocyte surface proteins, leading to complement activation and its spectrum of effects. We explore this case of a 57‐year‐old man with post‐essential thrombocythemia (ET) myelofibrosis (MF) who developed symptomatic anemia with evidence of hemolysis on lab work. While hemolysis was localized to be intramedullary based on workup, the exact diagnosis was undetermined, leading to a prolonged course of steroid therapy to control anemia. The hemolysis was eventually attributed to PNH diagnosed on flow cytometry and the patient was treated with complement inhibitors with eventual failure of therapy. He ultimately underwent a successful hematopoietic cell transplant (HCT) with post‐transplantation flow cytometry showing complete resolution of PNH. While PNH has been identified as a progression of myelodysplastic syndromes, the mechanisms of its rare development in myeloproliferative neoplasms are poorly elucidated. Furthermore, its rarity and often vague symptoms make diagnosis and treatment a challenge. This is the second reported case of a JAK2‐negative, CALR‐positive post‐ET MF and the first reported case to be treated with HCT. This case probes for further insight into the clinical significance between MF and PNH, its impact on management, and further consideration for HCT as curative therapy in such patients who fail complement inhibitor therapy.
2023-10-30 | The effect of thrombocytapheresis on hemogram and biochemistry parameters in patients with essential thrombocytemia.
Essential thrombocythemia is one of the chronic myeloproliferative neoplasms characterized by clonal proliferation of myeloid cells with variable morphological maturation and hematopoietic activity.It is characterized by excessive clonal platelet production with a tendency to thrombosis and bleeding. Thrombocytapheresıs is the removal of platelets by apheresis techniques. Thrombocytapheresıs is generally recommended in patients with essential thrombocythemia with acute, severe thrombotic or hemorrhagic events. The study included 39 patients who were diagnosed with essential thrombocythemia, started cytoreductive and aspirin therapy, and underwent thrombocytapheresıs due to the development of acute severe thrombotic or hemorrhagic events, diagnosed in the adult hematology clinic of İnönü University Turgut Ozal Medical Center. Hemogram and biochemistry values of the patients were scanned retrospectively. After thrombocytapheresıs, a statistically significant difference was found between the first and last measurements of hemoglobin, mean platelet volume, White blood cell, neutrophil, platelet, platelet distribution width, creatine, lactate dehydrogenase, fibronogen and calcium levels of the patients. The use of thrombocytapheresıs in patients with essential thrombocytosis causes a rapid decrease in platelet values as well as an effect on hemogram and biochemistry parameters. Other hemogram and biochemistry parameters such as platelet value should be monitored in patients.
2023-01-20 | [Durable remission following donor lymphocyte infusion for post-transplant relapse of acute myeloid leukemia developing from secondary myelofibrosis].
Essential thrombocythemia gradually developed into secondary myelofibrosis and progressed to leukemia eight months later in a 53-year-old man. After remission induction therapy, he achieved remission by undergoing allogeneic hematopoietic stem cell transplantation from unrelated patients in non-remission. However, peripheral blood WT-1 mRNA gradually increased, and the disease relapsed three years and six months after transplantation. He was taking prednisolone (7.5 mg) and tacrolimus (5 mg) for chronic pulmonary graft-versus-host disease (GVHD) and was reluctant to reduce or discontinue immunosuppressive drugs; therefore, donor lymphocyte infusion (DLI) was performed for a total of five times. Four months after the fifth DLI, cutaneous GVHD appeared, a slow decrease in WT-1 mRNA was observed, and blasts in the peripheral blood disappeared. One year and three months after the last DLI, he achieved complete remission. Although DLI for post-transplant relapse in patients with secondary myelofibrosis or leukemia is rare, it can be beneficial for post-relapse therapy.
2022-09-14 | The safety and performance of the Spectra Optia apheresis system platelet depletion protocol in patients with elevated platelet counts
Abstract Background Thrombocytosis is a presenting and progressive clinical feature found in multiple disease states. It is characterized by high platelet (PLT) counts (>450 × 10 9 /L) and can lead to thrombohemorrhagic events. Thrombocytapheresis or platelet depletion (PLTD) can be performed in acutely symptomatic patients suffering from thrombocytosis and may reduce or prevent acute serious complications associated with thrombocythemia thereby enabling patients to receive potentially curative high‐dose chemotherapy. Methods This report details the results from 2 clinical studies, one conducted in the European Union (EU) and one in the People's Republic of China, assessing the PLTD procedure on the Spectra Optia Apheresis System. The primary objective of both studies was to assess the safety and performance of the PLTD procedure in patients with elevated PLT counts. Results Data were collected from 56 participants completing 64 PLTD procedures. The mean percent change in PLT count and collection efficiency (CE1) was 55.1% and 68.5%, respectively. In the EU study, 6 participants experienced a total of 9 adverse events (AEs) and in the China study, 44 participants reported a total of 212 AEs. In both studies, the majority of AEs reported were Grade 2 or lower and no serious AEs, unanticipated adverse device effects, or AEs leading to death were reported. Conclusions The data collected within these studies indicate that the PLTD procedure is well tolerated and effective at reducing circulating PLTs in patients suffering from thrombocytosis as evaluated by a percent decrease in PLT count, CE1, and AE incidence.
proteins
2026-09-17 | Interferon-α vs hydroxyurea in patients with myeloproliferative neoplasms (DALIAH): a multicentre, randomised, open-label, phase 3 trial in Denmark.
Hydroxyurea (HU) is the most commonly used cytoreductive treatment for patients with myeloproliferative neoplasms (MPN), but emerging data on pegylated interferon-alpha2 (pegIFNα) are encouraging. Optimal first-line treatment remains unclear. DALIAH was a randomised, open-label, parallel-group, phase 3 trial conducted at nine centres in Denmark comparing HU with pegIFNα in patients with newly diagnosed MPN. Adults (≥18 years) with newly diagnosed or cytoreductive treatment-naïve MPN (essential thrombocythaemia [ET], polycythaemia vera [PV], prefibrotic myelofibrosis [pre-PMF], or primary myelofibrosis [PMF]; according to 2008 World Health Organization [WHO] criteria) and evidence of active disease were eligible, regardless of risk score. Patients aged >60 years were randomised (1:1:1) to either HU, pegIFNα-2a, or pegIFNα-2b; patients aged ≤60 years were randomised (1:1) to either pegIFNα-2a or pegIFNα-2b. The primary endpoint was the proportion of molecular responders (MR; partial or complete) at 18, 36, and 60 months (intention-to-treat [ITT], HU vs pegIFNα). This trial was registered with ClinicalTrials.gov, NCT01387763. Between Feb 7, 2012, and July 6, 2015, 203 eligible participants were enrolled in the modified ITT population (HU n = 38 [19%], pegIFNα n = 165 [81%]). In the ITT analysis, MR proportions were similar between HU and pegIFNα at 18 months (19% vs 21%, p = 1·00), 36 months (19% vs 26%, p = 0·64), and 60 months (23% vs 24%, p = 1·00). In the per-protocol (PP) analysis, restricted to patients who remained on therapy, pegIFNα showed higher MR beyond 36 months (36 months: 23% vs 56%, p = 0·01; 60 months: 35% vs 67%, p = 0·03). At month 60, PegIFNα discontinuation was high (65% vs 37% HU, p = 0·0019). No significant difference in grade ≥3 adverse events was observed between groups (HU 58% vs pegIFNα 45%, p = 0·21). Adverse events occurring in ≥10% of patients differed between treatments: dyspepsia, pyrexia, and urinary tract infections were more common with HU, whereas fatigue, influenza-like illness, injection-site irritation, myalgia, and decreased white cell blood count were more frequent with pegIFNα. Anaemia and decreased neutrophil count were the most common haematological events in both groups. Treatment-related adverse events were reported in 77 patients (HU 27% vs pegIFNα 41%, p = 0·14) and led to permanent discontinuation in 13 patients (all pegIFNα). HU and pegIFNα display distinct response kinetics. Molecular response was similar in the ITT analysis, reflecting that non-response largely resulted from higher pegIFNα discontinuation rather than lack of efficacy. Among patients who tolerated therapy, pegIFNα achieved superior long-term molecular responses. Findings should be considered within the context of the significantly higher treatment discontinuation rate with pegIFNα than with HU. These findings suggest that pegIFNα may offer long-term molecular benefit in selected patients highlighting the need for biomarkers that predict response and long-term tolerability, preferably already at diagnosis. OUH-Region Sjaelland Faelles Forskningspulje, Region Sjællands Sundhedsvidenskabelige Forskningsfond (RSSF) 2018, Gangstedfonden, OUH Frie Forskningsmidler, Swedish Orphan, Fonden til Lægevidenskabens Fremme, Ellen og Aage Fausboells Helsefond af 1975, and Desirée og Niels Ydes Fond.
2026-08-26 | Pregnancy Transiently Normalized Platelet Counts in Essential Thrombocytosis.
Outcomes of pregnancies complicated by essential thrombocytosis (ET) are worse than those of normal pregnancies. Aspirin, heparin, and interferon (IFN)-α are well-tolerated during pregnancy and prescribed in accordance with the risk of thrombosis. However, some evidence suggests that platelet count decreases during ET-complicated pregnancies. We retrospectively analyzed changes in platelet count in ET-complicated pregnancies. Platelet count decreased during pregnancy without IFN-α use, and 83% of pregnant women had a platelet count of ≤450×109/L. Furthermore, all pregnant women achieved a platelet count of ≤600×109/L. One the basis of revised IPSET-thrombosis score, risk was classified as low or very low. Aspirin use starting in early pregnancy was associated with a higher rate of successful delivery, even in patients with prior miscarriage. These findings suggest that platelet counts decrease in selected low-risk and very-low-risk ET-complicated pregnancies and that cytoreductive therapy with IFN-α may be avoidable in some cases. These results should be interpreted cautiously because of the small sample size and retrospective study design.
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.
2026-06-17 | Ropeginterferon alfa-2b-njft treatment in essential thrombocythemia across different driver mutations: results from a North American, single-arm, multicentre study (EXCEED-ET).
Ropeginterferon alfa-2b-njft (ropeg), a mono-PEGylated interferon-α, showed efficacy and safety in patients with hydroxyurea-intolerant/resistant essential thrombocythemia (ET) in the phase 3 SURPASS-ET largely conducted in Asia. Here we report the results from the EXCEED-ET study, which evaluated ropeg in both treatment-naïve and hydroxyurea pre-treated ET in North America. The single-arm, multicentre, phase 2b trial EXCEED-ET was conducted at 28 centers in the United States and Canada. Patients with ET enrolled were required to have a platelet count >450 × 109/L at screening. Patients were eligible regardless of prior cytoreductive therapy status and included both treatment-naïve and hydroxyurea-pretreated patients. Ropeg was subcutaneously administered in an accelerated titration schedule at 250 μg at Week 0, 350 μg at Week 2, and 500 μg from Week 4 and beyond. The primary endpoint was durable, modified European LeukemiaNet (ELN) response at both Months 10 and 13 (ClinicalTrials.gov identifier: NCT05482971). Between January 17, 2023, and May 15, 2025, 106 patients were screened and 91 were enrolled. At baseline, participant median age was 57 years (range, 22-84) with 57/91 (62.6%) being female and 71/91 (78.0%) being White. Among 91 patients enrolled, durable modified ELN response rate was 60.2% (95% CI, 49.0-71.4). The median time to hematologic response was only 8.4 weeks (95% CI: 8.1-11.9). Splenomegaly and symptom improvement or non progression occurred in 90/91 (98.9%) and 71/91 (78.0%), respectively. Seven of 91 (7.7%) patients with palpable spleen at baseline and all had an improvement in disease-related signs. The rates of molecular response for driver mutations at Month 13 as defined by ELN2009 criteria were 35.0% (7/20) for patients with JAK2V617F, 16.0% (4/25) for CALR, and 25.0% (2/8) for MPL mutations. One (1/1) TP53 mutation-positive patient showed a complete molecular response. Thrombosis and progression occurred in 3.4% (3/91) and 1.1% (1/91), respectively. Most treatment-emergent adverse events were mild, including fatigue (60%) and reversible transaminase elevations (58%). There was no grade 5 TEAE and one (1.1%) grade 4 TEAE (hepatitis toxic) which recovered without sequelae. Grade ≥3 TEAEs occurred in 27.5% (25/91) of the participants, most commonly with alanine aminotransferase and aspartate aminotransferase increases (4.4%; 4/91), neutrophil count decrease (4.4%; 4/91), fatigue (3.3%; 3/91) and lymphocyte count decrease (3.3%; 3/91). Treatment-related serious adverse events occurred in 5.5% (5/91) of patients. Pneumonia was the most common SAE, occurring in 2/91 (2.2%) patients. Ropeg-related discontinuations occurred in 9/91 (9.9%) patients. Ropeg showed efficacy and substantial molecular responses with good overall tolerability across a broad ET population. PharmaEssentia.
2026-04-17 | Essential Thrombocythemia-Associated Distal Radial Pseudoaneurysm Treated With Thrombin Injection.
Distal radial artery access is associated with a low complication rate and infrequently leads to pseudoaneurysm formation. Consequently, the clinical characteristics of pseudoaneurysms in essential thrombocythemia (ET) are not well characterized. A 79-year-old woman with ET developed a pulsatile wrist mass 2 weeks after coronary angiography via distal radial artery access. Imaging revealed a 17-mm pseudoaneurysm. Conservative compression was unsuccessful. The initial thrombin injection resulted in partial thrombosis with distal escape and re-entry flow. A subsequent injection with manual proximal radial compression achieved complete thrombosis without complications. In ET, qualitative platelet dysfunction may compromise thrombus stability after thrombin injection. Proximal radial compression is crucial in distal radial pseudoaneurysms to prevent distal escape and achieve durable thrombosis. Because ET can compromise thrombus stability, sufficient inflow reduction is essential for successful thrombin injection in distal radial pseudoaneurysms.
antibodies
2026-08-19 | Immunotherapeutic targeting of calreticulin mutant myeloproliferative neoplasms.
Calreticulin (CALR) frameshift mutations drive the majority of JAK2/MPL-wild-type cases of essential thrombocythemia and myelofibrosis, producing a shared novel C-terminus that activates the thrombopoietin receptor and leads to constitutive Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. CALR mutations transform the multifunctional endoplasmic reticulum (ER)-resident protein into an oncogenic driver that aberrantly traffics to the cell surface, activates the thrombopoietin receptor, MPL, and promotes MF megakaryocytic proliferation and hemopoietic stem cell fitness. Clinically, CALR-mutated MPNs affect younger patients, exhibit thrombocytosis and progressive anemia, and, in MF patients, are associated with a superior survival compared with JAK2- or MPL-mutated disease, yet responses to hydroxyurea and ruxolitinib remain inferior. The C-terminal motif shared between CALR mutations is presented extracellularly on major histocompatibility complex (MHC) Class I molecules and in complex with the thrombopoietin receptor enabling targeting with vaccination and antibody based therapeutic platforms, respectively. Mutant CALR peptide vaccines induce T cell responses but have failed to result in hematologic or molecular responses. Mutant CALR-specific monoclonal antibodies, such as Fc-silent antagonists, can block mutant-CALR-MPL signaling, suppress hematopoietic stem and progenitor cells (HSPC) proliferation and megakaryopoiesis, and achieve rapid, durable hematologic remissions with minimal toxicity in early-phase trials. Preclinical antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor T cell (CAR-T) cells also show potent, selective mutant-cell killing. Here we review the basis and ongoing translational and clinical efforts in the development of CALR-targeted immunotherapies that offer a potential shift from symptom management to disease-modifying treatment in this molecularly defined MPN subset.
2026-04-20 | From JAK to CALR: redefining therapeutic targets in myeloproliferative neoplasms.
This review highlights the emergence of CALR as a promising therapeutic target in CALR-mutated myeloproliferative neoplasms. While current JAK inhibitors alleviate symptoms and reduce thrombosis risk, they lack clonal specificity, have a limited impact on the natural history of disease, and are limited by toxicity and resistance. In contrast, CALR mutations generate a unique, disease-specific neoepitope that drives disease pathogenesis through aberrant MPL activation and is accessible on the cell surface, making it an ideal immunologic and antibody target. Preclinical and early clinical advances - including monoclonal antibodies, bispecific T-cell engagers, CAR-T therapies, antibody-drug conjugates, and peptide/viral vector vaccines - have demonstrated selective activity against CALR-mutant clones while sparing normal hematopoiesis, with encouraging evidence of molecular remissions and disease modification. Although challenges such as immune tolerance remain, mutant CALR-directed therapies represent a potential transformative shift in essential thrombocythemia, and primary myelofibrosis treatment.
2025-08-26 | Novel strategies targeting mutant calreticulin in essential thrombocythemia and myelofibrosis.
The discovery of calreticulin (CALR) mutations in patients with myeloproliferative neoplasms (MPNs) has paved the way for the elucidation of a unique disease mechanism that is particularly well suited to targeting by biologics. All MPN-associated pathogenic CALR mutations are characterized by a frameshift, resulting in translation of the same neoantigen peptide. This neoantigen directly activates the thrombopoietin receptor, leading to uncontrolled neoplastic cell proliferation. Current therapeutic approaches for MPNs are focused primarily on blood count control. Furthermore, current approaches are neither disease modifying nor clonally selective. However, because the mutant CALR neoantigen peptide is functional and not expressed in normal physiology, it is an ideal drug target. Here, we review the structure and function of mutant CALR, including the subtle yet clinically and therapeutically relevant differences between the 2 most commonly occurring types of mutation. We also review the current therapeutic landscape for CALR-mutated MPNs, highlighting the areas in which current approaches are inadequate. Finally, we review ongoing clinical and preclinical experimental approaches for targeting mutant CALR in MPNs in a clonally selective manner using monoclonal antibodies, bispecific antibodies, cancer vaccination, chimeric antigen receptor T cells, and antibody-drug conjugates. Taken together, we expect that ongoing developments in mutant CALR-targeted therapeutics will lead to promising novel strategies for long-term disease control.
2025-03-29 | Tailored Treatments: Utilizing Anti-TNFs for Ankylosing Spondylitis and Essential Thrombocytosis
Thrombocytosis is a condition that is often detected incidentally and can be seen both in the course of myeloproliferative diseases (MPD) and as a reactive condition. Ankylosing spondylitis (AS) is a chronic multisystemic inflammatory disease that mainly affects the spine. Mild to moderate thrombocytosis may occur secondary to the course of AS. In the treatment of AS, tumor necrosis factor inhibitor (anti-TNF) treatments are actively used as first-line therapy. The number of cases of MPDs occurring in the course of AS reported in the literature is limited. Although the exact effect of anti-TNF treatment on the MPD process is not fully known, there are publications stating that caution should be exercised in cases of MPD. By this case, we wanted to share our experience of using anti-TNF therapy in a patient diagnosed with ET in the course of AS. The 35-year-old male patient had been diagnosed with AS for 11 years and had been followed up by hematology with the diagnosis of essential thrombocytosis (ET) since 2010. When there was no response to indomethacin and sulfasalazine treatments, the patient was first given etanercept, and after secondary unresponsiveness, infliximab and adalimumab treatments were given. Despite the use of multiple anti-TNFs, no hematological deterioration was detected in terms of ET. Clinical and laboratory responses were also obtained in terms of AS. The patient has been stable and in remission in terms of both AS and ET since 2016.
2025-02-17 | CALR-mutated myeloproliferative neoplasms.
Calreticulin (CALR) is a chaperone protein that plays a crucial role in protein folding quality control and calcium homeostasis. Mutations in CALR result in a mutated protein lacking key calcium-binding sites and the KDEL sequence, leading to a constitutive activation of the MPL-JAK2-STAT5 pathway, which is involved in the pathogenesis of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Despite advancements in understanding the role of CALR mutations, current therapeutic strategies remain focused on managing symptoms and complications, with allogeneic stem cell transplantation (alloHSCT) as the only curative option. Emerging research is exploring novel immunotherapeutic approaches targeting mutant CALR, including the development of anti-CALR antibodies and T-cell receptor-mediated therapies, offering potential new avenues for treatment in CALR-mutated MPNs. In this review, we will discuss on the role of CALR in MPNs, focusing on its biological structure and its implications on the prognosis and treatment of essential thrombocythemia and primary myelofibrosis.
other
2026-01-14 | Polycythemia Vera and Essential Thrombocythemia: A Nationwide Population-Based Study on Treatment Patterns, Vascular Complications and Survival.
Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with a well-recognized increased risk of thrombotic events, bleeding, and all-cause mortality, but the frequency of these outcomes during treatment has rarely been assessed in large cohorts. In this nationwide, population-based study, we analyzed 2604 PV and 3141 ET patients using multiple Swedish health care registers, covering 43 612 patient-years. Rates of arterial and venous events, major bleeding, and all-cause mortality (ACM) were evaluated across therapies. Unexpectedly, 42.3% of low-risk PV patients and 29.7% of very low/low-risk ET patients received hydroxyurea (HU) during follow-up. High-risk PV patients treated with interferon (IFN) exhibited the lowest arterial event rate (2.21 per 100 patient-years). In high-risk ET, patients with IFN therapy experienced the lowest arterial and venous event rates (1.55 and 0.44 per 100 patient-years). Advanced age and leukocytosis at diagnosis independently predicted thrombosis, bleeding, and ACM in both PV and ET. Multivariable analysis showed that HU and IFN were associated with reduced ACM risk; HU also conferred protection against thromboembolism and major bleeding. This study highlights risk factors associated with complications during treatment in a real-world context and reinforces the role of HU and IFN as first-line therapies in PV and ET.
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.
2025-03-21 | Imetelstat in myeloid malignancies: current data and future directions.
Telomerase reactivation allows cancer cells to maintain telomere length and evade senescence, making it an appealing therapeutic target. Imetelstat, an antisense oligonucleotide, is the first clinically effective telomerase inhibitor approved by the FDA and the European Commission for treating anemia in transfusion-dependent low-risk myelodysplastic syndromes (MDS). Sources for this review were identified through searches of PubMed, ClinicalTrials.gov, and conference abstracts. This review highlights the pharmacology, efficacy, and ongoing trials of imetelstat in treating MDS, myelofibrosis, essential thrombocythemia, and other malignancies. In the IMerge trial, imetelstat induced durable transfusion independence in heavily transfused LR-MDS patients. Pilot trials in myelofibrosis suggest imetelstat's potential disease-modifying properties and survival benefit, warranting further studies of imetelstat as a monotherapy or in combination therapies. Imetelstat can cause thrombocytopenia, leukopenia, elevated liver enzymes, and infusion reactions, which are mostly reversible but may rarely lead to fatal events. Future clinical trials in LR-MDS should focus on optimal sequencing and combination strategies for imetelstat with other agents, and identifying biomarkers that can predict response. Monitoring real-world outcomes will offer valuable insights into imetelstat's safety and efficacy in patient populations underrepresented in clinical trials. Imetelstat's role in other malignancies, especially myelofibrosis, is being explored.
2024-06-04 | Decreasing circ_0014614 promotes the differentiation of bone marrow flineage cells into megakaryocytes in essential thrombocythemia via activiation of miR-138-5p/caspase3 axis.
Circular RNAs (circRNA) are pivotal in hematological diseases. Previous study showed that circ_0014614 (circDAP3) was significantly underexpressed in bone marrow-derived exosomes from essential thrombocythemia (ET) patients, affecting the differentiation of bone marrow lineage cells into megakaryocytes. Fluorescence in situ hybridization (FISH) was used to display circ_0014614's primary cytoplasmic location in K562 cells. Cytoscape software was used to predict the circRNA-miRNA-mRNA networks, and their expression at the cellular level was detected by Quantitative reverse transcription-polymerase chain reaction (qRT-PCR). qRT-PCR was utilized to detect the expression levels of circ_0014614，miR-138-5p and caspase3 mRNA. Western blot was used to determine the protein levels of GATA-1, RUNX-1, NF-E2, CD41 and caspase3. The proliferation of K562 cells was assessed using the Cell Counting Kit-8 (CCK-8) Assay. Furthermore, the interplay between miR-138-5p and circ_0014614 or caspase3 was elucidated through a Dual-luciferase reporter assay. FISH assay indicated circ_0014614's primary cytoplasmic location in K562 cells. In ET bone marrow and K562 cells, circ_0014614 and caspase3 were down-regulated, whereas miR-138-5p saw a significant surge. Overexpressing circ_0014614 curtailed K562 cells' proliferation and differentiation. Further, circ_0014614 targeted miR-138-5p, with heightened miR-138-5p levels counteracting circ_0014614's inhibition. MiR-138-5p further targeted caspase3, and caspase3 silencing neutralized suppressed miR-138-5p's effects on K562 cell differentiation. Circ_0014614 was down-regulated in ET bone marrow and bone marrow lineage cells, and upregulating circ_0014614 can inhibit bone marrow lineage cells' proliferation and differentiation into megakaryocytes. Mechanistically, circ_0014614 functioned as ceRNA via sponging miR-138-5p and alleviated the inhibitory effect of miR-138-5p on its target caspase3, which potentially deters tumor activity in ET.
2023-10-31 | 1138 TGFβ-specific T cells recognize megakaryocyte progenitors in patients with myeloproliferative neoplasms
Background
Chronic myeloproliferative neoplasms (MPN) are a group of diseases that are characterized by the hyperproliferation of mutated hematopoietic stem cells (HSCs) in the bone marrow. Clinically, they can progress to myelofibrosis and acute myeloid leukemia. Megakaryocytic hyperplasia is known to drive fibrotic progression through the secretion of fibrosis-promoting factors such as transforming growth factor beta (TGFβ). Previous work from our group has demonstrated the existence of proinflammatory TGFβ-specific CD4+ and CD8+ T cells that are able to recognize and react towards cancer cells and autologous myeloid cells in a TGFβ-dependent manner. In this study, we investigated the presence of TGFβ-specific T cells in patients with MPN and examined their ability to target key cell types involved in the disease pathogenesis, including megakaryocyte progenitors.
Methods
T-cell responses towards a TGFβ-derived peptide epitope were assessed in peripheral blood mononuclear cells (PBMCs) from 102 patients with MPN and 34 healthy donors (HDs) using interferon gamma (IFN-γ) ELISPOT and intracellular cytokine staining. TGFβ-specific CD4+ T-cell cultures were generated from several patients with MPN by enrichment of reactive T cells following in vitro stimulation and subsequent rapid expansion. Autologous megakaryocyte progenitors were generated through in vitro differentiation of HSCs and expression of megakaryocytic surface markers was demonstrated using flow cytometry. The functional recognition of autologous megakaryocyte progenitors by TGFβ-specific CD4+ T cells was assessed through co-culturing and subsequent intracellular cytokine staining. The production of TGFβ in megakaryocyte progenitors was quantified using ELISA and western blotting.
Results
We describe the presence of TGFβ-specific CD4+ T cells in patients with MPN. We demonstrate stronger TGFβ-specific T-cell responses in patients with essential thrombocythemia (ET) as compared to both HDs and patients with polycythemia vera (PV) or primary myelofibrosis (PMF). We show that TGFβ-specific T cells initiate a proinflammatory cytokine response upon recognition of autologous megakaryocyte progenitors. We validate that these megakaryocyte progenitors produce significant amounts of TGFβ and express human leukocyte antigen (HLA)-class II on their surface. We are currently investigating the presence of TGFβ-specific T cells in the bone marrow of patients with MPN using T-cell receptor (TCR) sequencing.
Conclusions
Our findings highlight the ability of TGFβ-specific T cells to directly target megakaryocyte progenitors, which is a key cell type contributing to the manifestation and progression of disease in patients with MPN. As such, these results warrant further investigation into TGFβ-based immunomodulatory vaccination in patients with MPN.
Ethics Approval
Patient protocols were approved by the scientific ethics committee for the Capital Region of Denmark. Subjects gave written informed consent to participate in the study before taking part.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
11 orphan drug designations for Essential thrombocythemia, including 2 approved therapies.
11 orphan drug designations for Essential thrombocythemia, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
recombinant fully human IgG1 monoclonal antibody selectively targeting PD-L2 | antibodies | FDA | — | mAbTree Biologics AG |
peginterferon alfa-2a | proteins | FDA | Pharma& U.S. Inc. | |
Ropeginterferon alfa-2b | proteins | EMA | Aop Orphan Pharmaceuticals GmbH | |
Hetrombopag olamine, Rafutrombopag | — | FDA | Jiangsu Hengrui Pharmaceuticals Co., Ltd. | |
Bomedemstat ditosilate | small molecules | EMA | Merck Sharp & Dohme B.V. | |
bomedemstat | small molecules | FDA | Merck & Co., Inc. | |
ropeginterferon alfa-2b-njft [Besremi] | proteins | FDA | Approved | PharmaEssentia |
Pomalidomide | — | EMA | Celgene Europe Limited | |
ruxolitinib phosphate | small molecules | FDA | Incyte Corporation | |
Anagrelide hydrochloride monohydrate [Xagrid] | small molecules | EMA | [INACTIVE] Shire Pharmaceutical Development Limited | |
Anagrelide [Agrylin] | small molecules | FDA | Approved | Takeda Development Center Americas, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.