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.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by excessive production of one or more mature myeloid lineages. The JAK2 V617F point mutation - present in nearly all patients with polycythemia vera (PV) and in approximately 50% of those with essential thrombocythemia (ET) and primary myelofibrosis (PMF) - is the principal molecular driver in Philadelphia chromosome (Ph)-negative MPNs. This review, conducted in accordance with PRISMA 2020 guidelines, aimed to evaluate the clinical manifestations (thrombosis, splenomegaly, and bleeding), hematological parameters, serum lactate dehydrogenase (LDH) levels, and risk of disease progression to acute leukemia or myelofibrosis associated with the JAK2 V617F mutation. A comprehensive literature search was performed across PubMed/MEDLINE, Embase, Scopus, and Web of Science for studies published between 2005 and 2025. Following screening of 1,100 candidate records, 10 primary studies encompassing 3,311 patients were included in the final synthesis. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). The included studies demonstrate that the majority of JAK2 V617F-positive MPN patients are older than 50 years, with no marked sex predilection. Splenomegaly and thrombotic events were frequently reported across cohorts. Serum LDH levels, hematocrit, and hemoglobin were consistently elevated, while leukocytosis was the predominant hematological finding, though white blood cell (WBC) counts varied widely across MPN subtypes. A minority of patients demonstrated disease transformation to acute leukemia or myelofibrosis. These findings underscore the central prognostic and diagnostic significance of JAK2 V617F in Ph-negative MPNs and highlight its value in clinical risk stratification and therapeutic monitoring.

Ruxolitinib remains first-line standard of care for symptomatic myelofibrosis, but resistance/intolerance develops in most patients. Three Janus kinase inhibitors (JAKis) have entered the post-ruxolitinib space via distinct pivotal trials. We systematically searched prospective trials evaluating JAKi in refractory adults with myelofibrosis. Efficacy was assessed across phase 3 trials, with safety integrating phase 2 and real-world data. Pooled ≥35% spleen volume reduction at week 24 was 32.7% (95% confidence intervals 27.3-38.6) for fedratinib, 15.8% (11.7-21.0) for momelotinib and 21.6% (13.8-32.3) for pacritinib 200 mg bis in die; pooled ≥50% Total Symptom Score reduction rates were 32.8% (27.4-38.7), 25.3% (20.2-31.3) and 32.4% (22.9-43.7) respectively. Across safety datasets (n = 1004 trial; n = 790 real-world), fedratinib showed the highest grade ≥3 anaemia (34.3%) and any-grade diarrhoea (56.6%), whereas momelotinib the lowest (8.0%). Pacritinib carried the greatest risk of grade ≥3 bleeding (11.2%). Discontinuation due to adverse events was comparable across agents (~16%-17%). Real-world evidence from five momelotinib cohorts (n = 580) identified nephrotoxicity (glomerular filtration rate decline 17%-29%) and peripheral neuropathy (4%-20%) as monitoring targets. Despite limitations from differing study designs, each post-ruxolitinib JAKi shows a distinct efficacy/safety fingerprint mapping onto a phenotype, guiding second-line choice by clinical factors and prior adverse events.

Myelofibrosis is an advanced myeloproliferative neoplasm that is biologically driven by constitutively active JAK-STAT signaling. Resultant effects on hematopoiesis and inflammatory cytokine signaling give rise to an array of clinical manifestations that include proliferative features, splenomegaly, constitutional symptoms, cytopenias, propensity towards leukemic transformation, and risk of thrombosis, with patients exhibiting a high degree of variability in regard to clinical course. This necessitates an individualized treatment approach that accounts for a variety of clinical and therapy-specific factors. JAK inhibitors have emerged as the cornerstone of therapy. With 4 agents now approved in the class, selecting the appropriate agent is of critical importance. In this review we discuss key variables that should be considered in the creation of a therapeutic plan for patients with myelofibrosis. We will review pharmacologic differences between available JAK inhibitors, discuss the patient factors that drive therapy decisions in myelofibrosis, and highlight emerging therapies in the field.

Background and objectives: Myeloproliferative neoplasms (MPNs) are blood cancers characterized by elevated blood cell counts, bone marrow fibrosis (BMF), and chronic inflammation, which drives disease progression. BMF results from disrupted collagen turnover in the bone marrow extracellular matrix (ECM), making its reduction or stabilization a key therapeutic goal. Non-invasive biomarkers reflecting collagen turnover could potentially improve early detection of BMF and monitor disease activity. Methods: We evaluated serum biomarkers of collagen turnover in 130 MPN patients (MPN subtypes: ET = 49, PV = 60, pre-PMF = 8, PMF = 13) included in the DALIAH trial (ClinicalTrials.gov identifier: #NCT01387763). Type I and type III collagen formation (PRO-C1 and PRO-C3) and MMP-degraded type I, III, and IV collagens (C1M, C3M, and C4M) were measured by ELISA in serum. Biomarker levels were compared to age- and sex-matched healthy individuals and were assessed according to disease subtypes, somatic driver mutations, JAK2V617F VAF, and fibrosis grade. Furthermore, we studied correlations between the biomarker levels and conventional hematological markers for disease activity, such as hemoglobin, white blood cell count (WBCs), platelet counts, and lactate dehydrogenase (LDH). Results: Baseline PRO-C3 (p = 0.0005) and C1M (p = 0.0102) were elevated in MPN patients compared to healthy individuals, whereas C3M was decreased (p < 0.0001). Patients with primary myelofibrosis (PMF) had higher levels of PRO-C3 compared to patients with ET (p = 0.0041) and PV (p = 0.0172), correlated with higher JAK2V617F VAF (≥50%) (p = 0.0069) and advanced fibrosis grade (p = 0.0002). In addition, PRO-C3 was positively correlated to LDH, which is a biomarker of disease activity in MPNs (r = 0.5754, p < 0.0001). Conclusions: Taken together, these findings emphasize the role of ECM remodeling in MPN pathophysiology and the potential of soluble ECM neoepitopes as biologically plausible disease markers.

Myelofibrosis (MF) is a biologically heterogeneous myeloproliferative neoplasm characterized by constitutive activation of the JAK-STAT pathway, progressive marrow fibrosis, cytopenias, splenomegaly, and systemic inflammation. Ruxolitinib, a JAK1/JAK2 inhibitor, remains the standard frontline therapy for intermediate- and high-risk MF, providing significant improvements in splenomegaly, constitutional symptoms, and survival. However, responses are highly variable, and a substantial proportion of patients experience suboptimal benefit, early discontinuation, or disease progression, underscoring the need for reliable predictors of treatment outcome. This review summarizes current evidence on clinical, molecular, cytogenetic, and dynamic predictors of ruxolitinib response in MF. Clinical variables, including cytopenic phenotype, peripheral blasts, baseline spleen size, symptom burden, prognostic risk category, timing of treatment initiation, and dose intensity, consistently influence treatment efficacy and durability. Notably, inadequate dose intensity emerges as the most relevant modifiable determinant of response. Molecular profiling further refines risk stratification: high-molecular-risk mutations, increased mutational burden, RAS/CBL pathway alterations, and adverse cytogenetics are associated with inferior outcomes, while driver mutation status alone has limited predictive value. The emergence of dynamic prognostic models such as RR6, iRR6, and STR-PM has enabled the integration of early treatment-related variables, including spleen response, transfusion dependence, and dose intensity, to identify patients at higher risk of treatment failure. These tools represent a shift from static baseline prognostication toward adaptive, response-oriented management. Emerging approaches integrating multi-omics profiling, circulating biomarkers, and artificial intelligence are warranted to further improve individualized decision-making among the expanding JAK inhibitor-based strategies in MF.

Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) characterized by endothelial injury and post-sinusoidal portal hypertension. Classical diagnostic criteria rely on clinical signs such as ascites, weight gain, and painful hepatomegaly; however, these features may be altered in patients with modified portal hemodynamics. We report the case of a 46-year-old woman with primary myelofibrosis who underwent transplantation after placement of a transjugular intrahepatic portosystemic shunt to manage severe portal hypertension. To our knowledge, this is the first reported case of VOD occurring after transplantation in a patient with a pre-existing transjugular intrahepatic portosystemic shunt, representing a unique diagnostic challenge. Early after transplantation, the patient developed rapidly progressive hyperbilirubinemia without the typical manifestations of VOD, leading initially to an alternative diagnostic hypothesis and delayed initiation of defibrotide therapy. The presence of the shunt likely attenuated hallmark clinical signs by decompressing the portal venous system, thereby masking the syndrome until advanced liver failure occurred. Despite treatment, the patient experienced progressive hepatic dysfunction and died. This case highlights a previously underrecognized diagnostic pitfall: standard diagnostic criteria for VOD may be unreliable in patients with altered portal circulation. Clinicians should maintain a high index of suspicion in this setting and consider early treatment when biochemical abnormalities emerge, as prompt recognition remains critical for improving outcomes.

Myeloproliferative neoplasms (MPNs) are broadly classified into BCR::ABL1-positive chronic myeloid leukaemia (CML) and BCR::ABL1-negative subtypes such as polycythaemia vera (PV), essential thrombocythaemia and primary myelofibrosis. Although traditionally considered mutually exclusive, rare cases of coexisting BCR::ABL1 rearrangement and Janus kinase 2 (JAK2) mutation have increasingly been recognised.We report the first Philippine case series of three patients with concurrent CML and JAK2-positive MPNs. Two patients developed PV 6-9 years after the initial diagnosis of CML despite ongoing tyrosine kinase inhibitor (TKI) therapy and molecular response, while a third patient had persistent thrombocytosis and was later found to have a concomitant JAK2-mutated MPN with fibrotic marrow features after 4 years.Compared with previously reported cases, our series demonstrates similarly delayed emergence of JAK2-mutated clones while highlighting real-world challenges in TKI intolerance, sequential TKI use and the need for combined cytoreductive strategies in a resource-limited setting.

The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis, are clonal hematopoietic stem cell disorders unified by constitutive thrombopoietin receptor (MPL) signaling. All 3 MPN driver mutations, JAK2, CALR, and MPL, converge on enhanced MPL signaling, establishing the thrombopoietin (TPO)/MPL axis as the central molecular hub linking clonal hematopoiesis to the cardinal manifestations of MPN, including thrombosis, hemorrhage, and fibrotic progression. As the principal regulator of hematopoietic stem cell maintenance and megakaryopoiesis and a key mediator of platelet priming, the TPO/MPL axis links stem cell biology to thromboinflammation and disease progression. This review summarizes the physiologic functions of the TPO/MPL axis, its dysregulation in MPN, and the downstream mechanisms linking aberrant MPL signaling to thrombosis, hemorrhage, and fibrotic progression. We further highlight recent advances in our understanding of TPO/MPL signaling in platelet biology, including its roles in platelet activation, metabolism, and thromboinflammation, and discuss emerging therapeutic strategies targeting the TPO/MPL pathway with the goal of simultaneously reducing thrombohemorrhagic complications, limiting fibrotic progression, and diminishing the malignant stem cell clone.

Data on real-world survival and treatment patterns in large, unselected myelofibrosis (MF) cohorts remain limited. We analysed 1649 patients with MF diagnosed from 2010 onwards and included in the Spanish Myelofibrosis Registry across 64 centres. Janus kinase (JAK) inhibitors were administered to approximately half of the patients. Among those aged ≤70 years with intermediate-2/high-risk International Prognostic Scoring System (IPSS), only 25% ultimately underwent transplantation. Median survival was 6.6 years, with no significant differences between primary and secondary MF; acute leukaemia was the most frequent cause of death, accounting for 20% of cases. Compared with a matched general population, relative survival at 5 and 10 years was 68% and 44% respectively. The reduction in relative survival was more pronounced in patients aged >65 years and in male patients, two subgroups that also exhibited a higher burden of comorbidities and a greater frequency of high molecular risk mutations. Remarkably, patients in the high-risk IPSS category had a 10-year relative survival of only 12%; however, survival reduction was not confined to high-risk disease, with divergence from expected survival emerging early among lower-risk categories. These findings highlight the persistent impact of MF on life expectancy in the contemporary JAK inhibitor era and the need for improvement in its overall management.

Pregnancy in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) is uncommon but clinically challenging. Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are clonal hematopoietic stem cell disorders characterized by myeloid proliferation, JAK-STAT pathway activation, and an increased risk of thrombotic and hemorrhagic complications. Pregnancy itself is a hypercoagulable state, and when it occurs in patients with MPNs, maternal and fetal complications are more frequent than in the general population. The most common fetal complications are first trimester pregnancy loss, placental insufficiency, fetal growth restriction, preeclampsia, preterm delivery, and stillbirth. Maternal complications include venous and arterial thrombosis, bleeding, acquired von Willebrand syndrome, and postpartum thromboembolism. ET is the most frequently encountered MPN in pregnancy and generally carries the most favorable prognosis. PV is associated with higher thrombotic and placental risk, largely related to erythrocytosis and hyperviscosity. Pregnancy in PMF is rare, and available data are limited to small series and case reports, making management particularly dependent on expert opinion. The mainstay of treatment is risk-adapted therapy with low-dose aspirin, low-molecular-weight heparin, phlebotomy for PV, and interferon-based cytoreduction when needed. Hydroxyurea, anagrelide, and JAK inhibitors are generally avoided due to limited fetal safety data. Given the paucity of prospective evidence, management should be individualized and coordinated by hematology and maternal-fetal medicine specialists. This review summarizes current data on MPN pregnancy outcomes and provides a practical approach to preconception counseling, antepartum management, delivery planning, postpartum care, and future research priorities.

Fusarium solani (F. solani), a ubiquitous environmental fungus and common phytopathogen, rarely causes cutaneous infections in humans-particularly in immunocompromised individuals, where it may lead to severe or disseminated disease with poor prognosis. We report a 60-year-old male with myelofibrosis on long-term ruxolitinib therapy, presenting with progressive cutaneous granulomas on the left thumb (duration: 6 weeks) and back (duration: 2 weeks). The diagnosis of cutaneous fusariosis was established based on clinical presentation, combined with fungal culture, morphological characterization and molecular identification of the pathogen from lesion exudates, crusts and excised tissue specimens obtained from both lesions. Multimodal therapy was initiated: empirical itraconazole combined with 5-aminolevulinic acid photodynamic therapy (ALA-PDT) for the thumb lesion, and surgical excision for the back lesion. Notably, although antifungal susceptibility later revealed itraconazole resistance, the patient showed marked improvement during combination therapy with itraconazole and PDT. Based on susceptibility results (terbinafine MIC < 0.03 μg/mL), the antifungal regimen was switched to terbinafine plus PDT. Complete remission was achieved with no recurrence at 6 month follow up. This case suggests that the multimodal regimen-combining systemic antifungal therapy, local ALA-PDT and surgical excision-may be an effective strategy for managing refractory cutaneous F. solani infection. However, the independent therapeutic contribution of ALA-PDT cannot be determined from a single case report.