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A 52-year-old gentleman presenting with tachycardia was found to have a large pericardial effusion and cardiac tamponade. This case was on a background of long-standing myelofibrosis managed with ruxolitinib, which was recently withheld for an orthopaedic procedure. He was diagnosed with presumed ruxolitinib discontinuation syndrome (RDS), resulting in a large pericardial effusion due to an increased inflammatory response. He was managed with a pericardial window and prompt recommencement of ruxolitinib and steroids. This case highlights the importance and increasing prevalence of RDS with the serious consequence of cardiac tamponade. Symptoms of RDS should be recognised and managed with recommencement of a JAK inhibitor and steroids.

Pharmacologic targeting of murine double minute 2 (MDM2) represents one of the most compelling strategies for therapeutic reactivation of wild-type p53 in hematologic malignancies. The MDM2-p53 autoregulatory loop is a central regulator of cellular stress responses, and in myeloid neoplasms-including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN)-p53 is frequently retained but functionally suppressed through MDM2 overexpression and oncogenic signaling, notably via JAK-STAT activation. Over the past decade, successive generations of MDM2 inhibitors have translated structural and mechanistic insights into clinical investigation, yielding critical lessons regarding dosing paradigms, hematologic toxicity, biomarker-driven patient selection, and mechanisms of resistance, including TP53-mutant clonal selection. While early phase III trials in AML were negative, recent studies in myelofibrosis demonstrate clinically meaningful spleen, symptom, and molecular responses, supporting disease-modifying potential in TP53-wild-type settings. Adaptive platform designs and rational combinations with JAK inhibitors, BCL-2 antagonists, and interferons have further refined therapeutic strategies. Emerging MDM2 degraders and next-generation agents aim to overcome feedback limitations and improve therapeutic index. This review integrates mechanistic foundations, clinical development, resistance biology, and future directions, highlighting how decades of basic science have reshaped p53 reactivation into a precision therapeutic paradigm in myeloid disease.

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.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive cytopenias, splenomegaly, and constitutional symptoms. The hallmark of MF pathophysiology is constitutive activation of JAK/STAT signaling, which, in the majority of cases, is associated with an acquired mutation in one of three driver mutations, JAK2, CALR, or MPL. Our growing understanding of the molecular biology of MPNs has resulted in regulatory approval of four JAK inhibitors (JAKi), which have demonstrated efficacy in improving symptom burden and reducing spleen size. Despite clear benefits of JAKi therapy, including evidence of improved survival, these therapeutic interventions have not established an ability to modify disease in terms of resolution of bone marrow fibrosis or molecular remissions. Therefore, recent emphasis has been on the development of novel therapies with informed targets outside of the JAK/STAT signaling pathway. Moreover, combination approaches utilizing JAK and non-JAK targeting agents underscore the potential for disease modification along with deeper and more durable clinical responses. Emerging combination strategies and their clinical development will be reviewed here, including investigations that pair JAKi therapy with BCL-2 family inhibitors, BET inhibitors, restored p53 cell death signals, telomerase inhibitors, PIM1 kinase inhibitors, and mutant CALR targeted therapies. While several combination clinical trials suggest improved spleen and symptom responses and the possibility of disease modification, toxicity profiles and optimal sequencing remain areas of active investigation.

High bone mineral density (BMD) is common and sometimes an incidental finding. The causes are numerous. Among them, none has previously been attributed to total body irradiation (TBI). We present the case of a 56-year-old female patient with a history of T-lymphoblastic lymphoma at age 33 who was treated with allogeneic hematopoietic stem cell transplantation following a conditioning regimen including a single-fraction 10 Gray TBI. This patient was in complete remission but experienced several transplant-related late effects. She presented to the rheumatology outpatient clinic with chronic mechanical low back pain and a history of early menopause. Bone assessment by densitometry revealed high bone mineral density with a lumbar spine L2-L4 T-score of +6.3 standard deviation (SD) (1.939 g/cm[2]), right femoral neck T-score of +7.2 SD (1.849 g/cm[2]), right total femur T-score of +4 SD (1.484 g/cm[2]), distal radioulnar T-score of +0.7 SD (0.495 g/cm[2]). Imaging revealed sclerotic lesions in the vertebrae, femoral cortices and pelvis. An etiological workup excluded other causes such as fluorosis, mastocytosis, renal osteodystrophy, hypoparathyroidism/pseudohypoparathyroidism and myelofibrosis. Bone growth factors and resorption markers were normal. Genetic sequencing showed no significant abnormalities. Based on this comprehensive evaluation, TBI was identified as a possible contributing factor to the occurrence of high BMD. The patient was managed with analgesics and regular follow-up. This case highlights the importance of a systematic etiologic approach to high bone mineral density and underscores the need for future scientific research to better understand this phenomenon for which the pathological relationship with radiation exposure remains unknown.

Philadelphia-negative myeloproliferative neoplasms (MPNs), encompassing polycythemia vera, essential thrombocythemia, and primary myelofibrosis, represent a group of chronic clonal hematopoietic disorders characterized by excessive proliferation of myeloid lineages and with a propensity for arterial and venous thrombosis. These disorders provide a unique human model of inflammation-driven, clone-mediated vascular disease with mechanistic insights highly relevant to cardiovascular medicine. The interplay of elevated hematocrit, leukocytosis, activated platelets, neutrophil extracellular traps, endothelial dysfunction, and chronic cytokine elevation creates a multifaceted prothrombotic state. Randomized evidence, such as the CYTO-PV (cytoreductive therapy in polycythemia vera) trial, demonstrates that correcting hematocrit meaningfully reduces major cardiovascular and thrombotic events. Discoveries like Janus Kinase 2 valine-to phenylalanine substitution on position 617-mutated clones, altered platelet biology, and NETosis inform evolving concepts in coronary artery disease, microvascular ischemia, and inflammatory thrombosis. This review synthesizes thrombosis biology in MPNs with actionable implications for cardiologists. Key lessons include the importance of clonal hematopoiesis as a cardiovascular risk factor, the role of inflammation and hematologic dysregulation in accelerating atherothrombosis, and the therapeutic relevance of antiplatelet optimization, hematocrit control, cytoreductive therapy, and anti-inflammatory interventions. The review also outlines diagnostic situations in cardiology where MPNs should be suspected, proposes opportunities for improved risk stratification, and identifies research priorities bridging the 2 specialties.

Novel therapies for myelofibrosis (MF) are needed, particularly after JAK inhibitor failure. This open-label, phase 1/2 study evaluated bomedemstat, an irreversible inhibitor of lysine-specific demethylase 1 (LSD1), in participants with MF refractory or resistant to, inadequately controlled by, or intolerant of approved therapies. Eighty-nine participants initially received bomedemstat 0.25, 0.5, or 0.6 mg/kg orally once per day titrated to achieve a target platelet count of ≥50 to ≤75 ´ 109/L. Primary end points were safety and change in spleen volume. Hematologic response and change in symptom burden, bone marrow fibrosis score, and variant allele frequency (VAF) were exploratory. Eighty-seven participants (97%) experienced ≥1 any-cause adverse event (AE), most commonly thrombocytopenia (48%) and dysgeusia (36%); 62 participants (69%) experienced ≥1 grade 3-5 AE. Three participants (3%) experienced AEs that led to death; none were related to treatment. Of 35 participants with spleen volume data at week 24, 23 (66%) had a reduction in spleen volume; 9 (26%) had a reduction of ≥20%. Mean platelet and white blood cell counts normalized over 24 weeks; hemoglobin levels remained stable. Participants reported improvement in most symptoms, including fatigue. Of 35 participants with baseline and week 24 data, 8 (23%) had improved bone marrow fibrosis by ≥1 grade per central review, and 21 (60%) were stable. Of 36 participants with CALR, JAK2, or MPL mutations and data at week 24, 56% had a reduction in VAF. Bomedemstat has manageable safety and clinical activity in participants with MF in need of an alternative therapy. This trial was registered at www.cinicaltrials.gov as #NCT03136185.