Idasanutlin is a small molecule inhibitor that restores p53 activity, triggering apoptosis. Two trials (phase 1/2) of idasanutlin therapy in polycythemia vera patients that were intolerant or refractory to hydroxyurea resulted in substantial clinical and molecular responses. Here the long term outcomes of these patients are reported.

Myeloproliferative Neoplasms (MPNs) are rare hematologic neoplasms. The epidemiology and outcomes of these rare neoplasms warrant an update considering new diagnostic tools and advances in treatment options. NCI's Surveillance, Epidemiology and End Result (SEER)-17 registries were interrogated to analyze adult patients diagnosed with MPN [ICD-O-3 codes: polycythemia vera (PV) 9950/3, essential thrombocythemia (ET) 9962/3, primary myelofibrosis (PMF) 9961/3, and chronic myeloid leukemia (CML) 9875/3] during the years 2000 to 2021. Data of 63,242 (ET, n=24 172; PV, n= 23 456; PMF, n=6 131; CML, n=9 483) patients were analyzed. The overall incidence rate (IR) for ET, PV, PMF and CML was 1.8, 1.7, 0.5 and 0.7 per 100 000 person-years respectively. The incidence of ET, PV, and MF increased with age, and majority of cases were seen after the age of 50. 5-year Relative Survival (RS) for PMF was 50.9% in 2009, to 57.4% in 2013 and 60.6% in 2016. The median overall survival (OS) was 152 months for ET, 150 months for PV, 48 months for PMF, and 202 months for CML. Advancing age was associated with adverse survival across MPN subtypes. Survival of patients with PMF continues to improve over recent years. Important racial and gender variations exist were noted in our study.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative approach in myelofibrosis (MF). Janus-Associated Kinase inhibitors (JAKi) have changed the treatment paradigm of MF patients, becoming a therapeutic mainstay in those with splenomegaly and/or constitutional symptoms. The impact of JAKi prior to allogeneic transplant is still under investigation. The aim of the current study was to analyze the outcome and prognostic factors, especially JAKi impact on transplantation outcome in MF patients. The study comprised 96 patients (64 - MF, 21 - post-polycythemia vera (PV), 11 - post-essential thrombocythemia (ET) at a median age of 54 years at transplant (44 females, 52 males) who underwent alloHSCT in years 2008-2025. Forty-seven patients (49%) had previously received JAKi with a median treatment duration of 11 months. Median follow-up after alloHSCT was 11 months. A 2-year probability of overall survival (OS) was 78.5% for JAKi exposed patients and 48.2% for JAKi naïve ones (p = 0.005), event free survival (EFS) was 70.0% and 46.2%, respectively (p = 0.02). A 2-year relapse incidence (RI) was 13.7% and 22.6% (p = 0.298) and non-relapse mortality (NRM) was 18.9% and 40.3% (p = 0.033) in JAKi and no-JAKi exposed group, respectively. Prior JAKi use was the only factor favorably impacting post-transplant overall survival both in uni- and multivariable analysis (p = 0.02 and p = 0.03, respectively). Low ECOG score and low HCT-CI positively affected survival. Transfusion dependency prior to alloHSCT was identified as an unfavorable factor. It was demonstrated that pre-transplant JAK inhibition significantly improved post-transplant overall survival. Patient's performance status and comorbidities are variables significantly affecting survival. Transfusion burden not only adversely impacts quality of life but was also found as an adverse factor in terms of EFS, NRM and RI.

A male castrated Shih Tzu was evaluated for recurrent nocturnal episodes of acute respiratory distress accompanied by hemoptysis and transient erythrocytosis. The dog was clinically normal between episodes, but each nighttime event was severe and prompted repeated emergency visits. During each emergency presentation, thoracic radiographs revealed severe diffuse interstitial-to-alveolar pulmonary infiltrates, and packed cell volume showed marked but reversible increases. A stepwise diagnostic evaluation, including serial indirect blood pressure measurement, coagulation assessment, echocardiography, and bronchoscopy with bronchoalveolar lavage, progressively excluded typical infectious, cardiac, structural, and coagulopathic causes of hemoptysis and acute respiratory distress. Given the stereotyped pattern of near-acute crises with diffuse pulmonary infiltrates and hemoptysis, mechanisms analogous to noncardiogenic pulmonary edema or exercise-induced pulmonary hemorrhage were considered. Therapeutic trials with sildenafil and furosemide failed to prevent further nocturnal recurrences. Considering concurrent transient PCV surges and the proposed role of catecholamine-driven splenic contraction as a rapidly mobilizable erythrocyte reservoir, a sympathetically mediated process was suspected, and α1-adrenergic blockade with prazosin was initiated. Following prazosin therapy, sustained clinical remission was achieved, with no further emergency episodes over a 17.5-month follow-up period. The response may have reflected multiple pharmacological effects of prazosin, including attenuation of sympathetically mediated splenic α1-adrenergic activity, systemic vasodilation, and reduction in venous return. This unique case suggests that dysregulation of the sympathetic nervous system may have contributed to the recurrent hemoptysis and acute respiratory distress and highlights adrenergic modulation as a potential therapeutic consideration in similar cases.

Erythropoiesis and iron metabolism are closely interconnected, under both physiological and pathological conditions. Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) caused by a Janus kinase-2 (JAK2) mutation, resulting in uncontrolled red blood cell production and elevated hemoglobin and hematocrit levels. In PV, iron deficiency is common and may be due to several factors, including chronic gastrointestinal bleeding, chronic inflammation, dysregulated hepcidin signaling, and therapeutic phlebotomy. Many patients exhibit low serum ferritin and low to normal hepcidin levels despite erythroid proliferation, suggesting a maladaptive iron-restricted state. This functional iron deficiency may limit erythropoiesis to some extent, but also contributes to burdensome symptoms such as fatigue, cognitive impairment, and restless leg syndrome. Novel therapeutic approaches, including hepcidin mimetics or ferroportin inhibitors, aim to restore iron homeostasis, improving quality of life and potentially reducing the need for cytoreductive therapy (drugs used to treat MPNs by reducing blood cell production) in low-risk PV patients. In secondary forms of erythrocytosis (both congenital and acquired), iron homeostasis has been less often investigated. However, exploring it may be of great interest since in these affections, iron overload could act as a hidden driver of erythrocytosis by stimulating erythroblast proliferation. Hereditary hemochromatosis (HH) is a well-known cause of iron overload. While its association with erythrocytosis has been a subject of interest, it remains incompletely understood. In this review, we will explore the complex relationship between iron (deficiency or overload, including HH) and erythrocytosis (including PV), discussing underlying mechanisms and potential therapeutic applications.

Ruxolitinib, a JAK1/JAK2 inhibitor, has demonstrated efficacy in achieving hematocrit control, spleen volume reductions, and symptom improvement in patients with polycythaemia vera (PV) resistant to or intolerant of hydroxyurea in clinical trials. PaVe is a prospective, noninterventional study of patients with PV who received ruxolitinib in a real-world setting in Germany. Observational parameters included effectiveness, safety, patient satisfaction and quality of life. Patients with and without prior treatment with ruxolitinib were included in this study. Additionally, patients were stratified by no/high risk. The study was primarily analyzed using descriptive methods. Four hundred and thirty-three patients with PV were included in this study, of which 62% were pretreated with a JAK-inhibitor and 38% were not. Mean decreases from Baseline in hematocrit levels/leukocyte counts at the last assessment were more pronounced in naïve patients (-6.2% versus - 1.6%/-4.5 × 103/µl versus - 1.4 × 103/µl) and high-risk patients (-6.3% versus - 5.3%/-4.8 × 103/µl versus - 2.6 × 103/µl). Mean decreases from Baseline in thrombocyte counts at the last assessment were more pronounced in naïve patients (-80.5 × 103/µl versus - 42.6 × 103/µl) and no-risk patients (-108.0 × 103/µl versus - 77.1 × 103/µl). There was almost no difference in the total number of thromboembolic events in JAK inhibitor naïve versus JAK inhibitor pretreated patients (3.1%, n = 5 versus 3.8%, n = 10). No new safety concerns were observed with ruxolitinib. Findings from this study in a real-world setting show that ruxolitinib is an effective and safe second-line treatment in PV patients.

Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm associated with thrombotic and vascular complications. Giant cell arteritis (GCA) is a granulomatous large-vessel vasculitis that may involve the aorta and can present as aortitis or aneurysm formation. Coexistence of PV and GCA is uncommon and may complicate diagnosis and management. We report a 41-year-old man with low-risk PV (JAK2 V617F-positive) who presented 4 months later with an ischemic stroke and was incidentally found to have a 5.0 cm ascending aortic aneurysm. Despite cytoreduction and surveillance, the aneurysm enlarged to 5.6 cm and was repaired electively. Histopathology of the resected aortic wall showed granulomatous inflammation with multinucleated giant cells and elastic lamina fragmentation, consistent with GCA. The patient had no cranial or systemic features suggestive of active GCA at diagnosis; therefore, systemic corticosteroids were deferred and close rheumatology follow-up was arranged. This case underscores the need to consider inflammatory aortitis/large-vessel vasculitis when atypical vascular findings occur in PV and highlights the value of multidisciplinary evaluation.

Myeloproliferative neoplasms (MPN) are hematological disorders driven by mutated hematopoietic stem cells, characterized by an increased risk of thrombosis and progression to leukemia. Patients with MPN exhibit elevated levels of inflammatory factors, which function as promoters of disease progression and transformation into acute leukemia. Fufang Huangbo formula (FHF) is a classic traditional Chinese herbal medicine widely used in the treatment of inflammation-related diseases, where it has shown considerable therapeutic efficacy. However, its potential effects on MPNs remain unclear. In this study, we demonstrate for the first time across multiple animal models that FHF significantly alleviates MPN progression, including EPO-induced polycythemia vera (PV)-like, JAK2[V617F]-driven PV, and MPL[W515L]-driven essential thrombocythemia (ET) models. FHF effectively reduced erythrocyte aggregation-induced thrombosis in PV and reversed myelofibrosis in ET. To explore the therapeutic effects, active components, and mechanisms of FHF in MPNs, we performed network pharmacology and RNA-seq analyses, with subsequent experimental validation. The results indicate that the therapeutic benefits of FHF are closely associated with cellular senescence and inflammatory responses. Validation experiments showed that FHF induces cellular senescence via activation of the p53/p21 pathway and suppresses inflammation by inhibiting the STAT3 and NF-κB signaling pathways. Our study provides scientific evidence supporting the use of FHF in the treatment of MPNs.