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This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.

Anagrelide (ANA) is a phosphodiesterase 3A (PDE3A) inhibitor, commonly prescribed for essential thrombocythemia. It also functions as a molecular glue, inducing complex formation between PDE3A and Schlafen 12. This association either triggers apoptosis or inhibits proliferation in tumor cells, supporting its use in cancer therapy. Conventionally administered orally, ANA undergoes rapid metabolism and elimination, resulting in a short drug exposure time at the site of action. Here, we explored the pharmacokinetic profile of a subcutaneously (SC) injected ANA formulation in Sprague-Dawley rats by quantifying plasma ANA and metabolite concentrations using liquid-chromatography-tandem mass spectrometry. We further evaluated the tumor regression efficacy of orally and SC administered ANA in a patient-derived gastrointestinal stromal xenograft mouse model - UZLX-GIST2B - characterized by a exon 9 driver mutation. The SC ANA exhibited extended-release plasma concentration-time profiles compared to intravenous and oral administrations. After a single administration in rats, plasma concentrations of ANA were detected up to 56 days later, and ANA metabolites up to 30 days later. The SC formulation also significantly reduced tumor volumes and demonstrated dose-dependent histological responses, nearly eradicating tumor tissue in 11 days with the highest dose. These findings suggest that the SC slow-release formulation maintains stable drug concentrations during treatment, potentially improving therapeutic efficacy at the target site.

Objective To evaluate the effectiveness and safety of anagrelide in Colombian patients with essential thrombocythemia (ET) treated under routine clinical practice conditions. Materials and Methods A prospective, multicenter, real‐world observational study was conducted across 15 departments in Colombia. Adult patients diagnosed with ET were included. Patients initiated treatment with anagrelide and were followed for 12 months. The primary outcome was the change in platelet count. Secondary outcomes included changes in hemoglobin, leukocyte counts, and reporting of adverse events. Response was classified as complete (< 400,000/μL), partial (400,000–600,000/μL), or absent (> 600,000/μL), adapted from ELN/IWG‐MRT criteria. Results Of the 103 patients recruited, 53 met the inclusion criteria. The mean age was 62.2 years, and 69.8% were female. Anagrelide was used as second‐line therapy in 88.7% of patients. At 12 months, 22.0% achieved complete response (< 400,000/μL) and 9.8% partial response (400,000–600,000/μL). Complete responses were more frequent in patients with dose escalation (38.2% vs. 9.5%; p = 0.0008). A progressive reduction in platelets was observed, particularly significant in those with baseline thrombocytosis > 600,000/μL (p < 0.001). No significant changes were identified in hemoglobin or leukocytes. Most adverse events were mild and consistent with the known profile of the drug: headache (39.6%), gastrointestinal symptoms (37.7%), and palpitations (26.4%). No serious treatment‐related events were reported. Conclusions In real‐world settings, anagrelide was effective and safe for the treatment of ET, yielding sustained platelet reduction and a favorable tolerability profile. Active dose titration was associated with higher response rates, underscoring the need for close monitoring in clinical practice.

Background Essential thrombocythemia (ET) is a myeloproliferative neoplasm commonly treated with hydroxyurea, while anagrelide is a second-line option. Although anagrelide has thrombocyte-specific action, its comparative efficacy remains debated. This systematic review and meta-analysis aimed to measure platelet reduction, thromboembolic events, and adverse events. Methods A systematic search of PubMed, Cochrane, Web of Science, Scopus, EMBASE, and CINAHL databases up to October 6, 2024, was conducted following the PRISMA guidelines. Randomized controlled trials and cohort studies comparing anagrelide and hydroxyurea were included. Results Six studies with 1555 participants met the inclusion criteria. Anagrelide was associated with significantly lower platelet counts than hydroxyurea (MD − 65.22; 95% CI − 80.78 to − 49.66; p < 0.01; I2 = 0%), but no significant difference in thrombohemorrhagic events (RR 1.34; 95% CI 1.10 to 1.62; p < 0.01; I2 = 12.5%). In single-arm analysis, JAK-positive patients showed a higher incidence of thrombotic events (0.23; 95% CI 0.14–0.35) than JAK-negative patients (0.10; 95% CI 0.08–0.13). Adverse event rates varied (RR 1.37; 95% CI 0.37–5.12; I2 = 94.9%). Conclusion Although comparative analyses against hydroxyurea have demonstrated the efficacy of anagrelide for platelet reduction in ET, its higher bleeding risk requires caution, especially in patients with risk factors. Further studies are needed to confirm long-term safety and refine dosing.

Opinion statementPolycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN), the ultimate phenotype of the JAK2 V1617F mutation, the MPN with the highest incidence of thromboembolic complications, which usually occur early in the course of the disease, and the only MPN in which erythrocytosis occurs. The classical presentation of PV is characterized by erythrocytosis, leukocytosis, and thrombocytosis, often with splenomegaly and occasionally with myelofibrosis, but it can also present as isolated erythrocytosis with or without splenomegaly, isolated thrombocytosis or isolated leukocytosis, or any combination of these. When PV is present, the peripheral blood hematocrit (or hemoglobin) determination will not accurately represent the actual volume of red cells in the body, because in PV, in contrast to other disorders causing erythrocytosis, when the red cell mass increases, the plasma volume usually increases. In fact, unless the hematocrit is greater than 59%, true erythrocytosis cannot be distinguished from pseudoerythrocytosis due to plasma volume contraction. Usually, the presence of splenomegaly or leukocytosis or thrombocytosis establishes the diagnosis. However, when a patient presents with isolated thrombocytosis and a positive JAK2 V617F assay, particularly a young woman, the possibility of PV must always be considered because of plasma volume expansion. The WHO PV diagnostic guidelines are not helpful in this situation, since the hematocrit is invariably normal and a bone marrow examination will not distinguish ET from PV. Only a direct measurement of both the red cell mass and plasma volume can establish the correct diagnosis. In managing a PV patient, it is important to remember that PV is an indolent disorder in which life span is usually measured in decades, even when myelofibrosis is present, that chemotherapy is futile in eradicating the disease but does increase the incidence of acute leukemia and that hydroxyurea is not safe in this regard nor is it antithrombotic. Phlebotomy to a sex-specific normal hematocrit is the cornerstone of therapy and there now exist safe remedies for controlling leukocytosis, thrombocytosis, and extramedullary hematopoiesis and symptoms due to inflammatory cytokines when this is necessary.

Melanoma, the deadliest type of skin cancer, has a high propensity to metastasize to other organs, including the brain, lymph nodes, lungs, and bones. While progress has been made in managing melanoma with targeted and immune therapies, many patients do not benefit from these current treatment modalities. Tumor cell migration is the initial step for invasion and metastasis. A better understanding of the molecular mechanisms underlying metastasis is crucial for developing therapeutic strategies for metastatic diseases, including melanoma. The cell adhesion molecule L1CAM (CD171, in short L1) is upregulated in many human cancers, enhancing tumor cell migration. Earlier studies showed that the small-molecule antagonistic mimetics of L1 suppress glioblastoma cell migration in vitro. This study aims to evaluate if L1 mimetic antagonists can inhibit melanoma cell migration in vitro and in vivo. We showed that two antagonistic mimetics of L1, anagrelide and 2-hydroxy-5-fluoropyrimidine (2H5F), reduced melanoma cell migration in vitro. In in vivo allograft studies, only 2H5F-treated female mice showed a decrease in tumor volume.

BackgroundIn Japan, anagrelide has been approved for use in patients with essential thrombocythemia. Here, the safety and efficacy of anagrelide was assessed in clinical practice as post-marketing surveillance. Subgroup analyses were conducted to compare patients (1) with or without a history of cytoreductive therapy (CRT), (2) <60 or ≥60 years of age, and (3) with an anagrelide starting dose of ≤0.5 mg/day or 1.0 mg/day.MethodsData were collected for all patients who received anagrelide, with an observation period of 12 months after treatment initiation.ResultsOf the 648 patients, 54.3% experienced adverse drug reactions (ADRs). The most commonly reported ADRs were headaches, palpitations, and anemia. No significant difference was observed in overall ADRs across patient subgroups. A significantly higher incidence of headaches was observed in patients < 60 years versus those ≥ 60 years (P < 0.001). The incidence of anemia and serious ADRs were significantly higher in patients ≥ 60 years, and those with a history of CRT (P < 0.05). The discontinuation rate at 6 months was significantly lower in patients started at the lower anagrelide dose (P < 0.05). Platelet counts decreased in all analyzed groups.ConclusionsThis surveillance showed that anagrelide has a tolerable safety and efficacy profile.

Myeloproliferative neoplasms arise from hematopoietic stem cells with somatically altered tyrosine kinase signaling. Classification of myeloproliferative neoplasms is based on hematologic, histopathologic and molecular characteristics including the presence of the BCR–ABL1 and JAK2 V617F. Although thought to be mutually exclusive, a number of cases with co-occurring BCR–ABL1 and JAK2 V617F have been identified. To characterize the clinicopathologic features of myeloproliferative neoplasms with concomitant BCR–ABL1 and JAK2 V617F, and define the frequency of co-occurrence, we conducted a retrospective multi-institutional study. Cases were identified using a search of electronic databases over a decade at six major institutions. Of 1570 patients who were tested for both BCR–ABL1 and JAK2 V617F, six were positive for both. An additional five patients were identified via clinical records providing a total of 11 cases for detailed evaluation. For each case, clinical variables, hematologic and genetic data, and bone marrow histomorphologic features were analyzed. The sequence of identification of the genetic abnormalities varied: five patients were initially diagnosed with a JAK2 V617F+ myeloproliferative neoplasm, one patient initially had BCR–ABL1+ chronic myeloid leukemia, while both alterations were identified simultaneously in five patients. Classification of the BCR–ABL1-negative myeloproliferative neoplasms varied, and in some cases, features only became apparent following tyrosine kinase inhibitor therapy. Seven of the 11 patients showed myelofibrosis, in some cases before identification of the second genetic alteration. Our data, reflecting the largest reported study comprehensively detailing clinicopathologic features and response to therapy, show that the co-occurrence of BCR–ABL1 and JAK2 V617F is rare, with an estimated frequency of 0.4%, and most often reflects two distinct ('composite') myeloproliferative neoplasms. Although uncommon, it is important to be aware of this potentially confounding genetic combination, lest these features be misinterpreted to reflect resistance to therapy or disease progression, considerations that could lead to inappropriate management.