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Annals of Hematology Jun 2024Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between... (Meta-Analysis)
Meta-Analysis
Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between JAK2V617F allele burden (also known as variant allele frequency) and the relevant clinical characteristics. Numerous studies have reported associations between allele burden and both hematologic and clinical features. While there are strong indications linking high allele burden in PV patients with symptoms and clinical characteristics, not all associations are definitive, and disparate and contradictory findings have been reported. Hence, this study aimed to synthesize existing data from the literature to better understand the association between JAK2V617F allele burden and relevant clinical correlates. Out of the 1,851 studies identified, 39 studies provided evidence related to the association between JAK2V617F allele burden and clinical correlates, and 21 studies were included in meta-analyses. Meta-analyses of correlation demonstrated that leucocyte and erythrocyte counts were significantly and positively correlated with JAK2V617F allele burden, whereas platelet count was not. Meta-analyses of standardized mean difference demonstrated that leucocyte and hematocrit were significantly higher in patients with higher JAK2V617F allele burden, whereas platelet count was significantly lower. Meta-analyses of odds ratio demonstrated that patients who had higher JAK2V617F allele burden had a significantly greater odds ratio for developing pruritus, splenomegaly, thrombosis, myelofibrosis, and acute myeloid leukemia. Our study integrates data from approximately 5,462 patients, contributing insights into the association between JAK2V617F allele burden and various hematological parameters, symptomatic manifestations, and complications. However, varied methods of data presentation and statistical analyses prevented the execution of high-quality meta-analyses.
Topics: Polycythemia Vera; Janus Kinase 2; Humans; Alleles; Gene Frequency; Amino Acid Substitution; Mutation, Missense
PubMed: 38652240
DOI: 10.1007/s00277-024-05754-4 -
Cureus Mar 2024Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by elevated platelet counts and fibrous tissues in the bone marrow. The JAK1/2 inhibitor...
Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by elevated platelet counts and fibrous tissues in the bone marrow. The JAK1/2 inhibitor (JAKi), ruxolitinib, has demonstrated efficacy in reducing splenic size, alleviating myelofibrosis-related symptoms, and improving overall survival. While an increased risk of lymphoproliferative disease (LPD) is suggested in patients with PMF, particularly those treated with JAKi, the involvement of Epstein-Barr virus (EBV) in such cases remains poorly documented. Here, we present the case of a 69-year-old woman with PMF who developed multiple lymphadenopathies and elevated soluble interleukin-2 receptor (sIL-2R) levels. Ruxolitinib and steroid therapy improved the symptoms for a short period; however, the lymphadenopathies and ascites eventually worsened. A biopsy confirmed EBV-positive diffuse large B-cell lymphoma, but the patient died of severe tumor lysis syndrome. Additionally, we conducted a literature review on EBV-related LPD in patients with primary and secondary myelofibrosis. Our report and literature review shed light on the occurrence of EBV-related LPD in MF, especially in those treated with JAKi, emphasizing the need to consider lymphoma as a potential diagnosis and monitor the EBV-DNA viral load in patients displaying lymphadenopathies or increased sIL-2R levels.
PubMed: 38646256
DOI: 10.7759/cureus.56586 -
Indian Journal of Nephrology 2024Proliferative glomerulonephritis in myelofibrosis is a very rare. Mesangial proliferation and sclerosis with changes of chronic thrombotic microangiopathy have been...
Proliferative glomerulonephritis in myelofibrosis is a very rare. Mesangial proliferation and sclerosis with changes of chronic thrombotic microangiopathy have been reported, but pauci-immune focal crescentic glomerulonephritis has not been described so far. Herein, we present a 68-year-old male who was a known case of myelofibrosis and presented with rapidly progressive glomerulonephritis and nephrotic range proteinuria. He was diagnosed as anti-neutrophil cytoplasmic antibody (ANCA)-negative focal crescentic glomerulonephritis, and he responded well to a course of intravenous methylprednisolone and cyclophosphamide. Pauci-immune focal crescentic glomerulonephritis may occur in myelofibrosis without ANCA and may be related to unknown pathogenetic mechanisms in myeloproliferative disorders or suggest any superimposed pathology that might respond well to immunosuppressants.
PubMed: 38645909
DOI: 10.4103/ijn.ijn_218_22 -
Clinical Medicine (London, England) May 2024Megakaryocytes are large multilobulated precursor cells which usually reside within the bone marrow and give rise to platelets. There have been rare occurrences where...
Megakaryocytes are large multilobulated precursor cells which usually reside within the bone marrow and give rise to platelets. There have been rare occurrences where they have been found in peripheral blood and extramedullary tissues in conditions where the underlying mechanisms of the bone marrow have been affected. This case report discusses an unusual presentation of a man with myelofibrosis who was found to have megakaryocytes in his ascitic fluid. We have highlighted the images showing utility of combination of traditional staining methods and immunohistochemistry in combating this diagnostic dilemma.
Topics: Humans; Primary Myelofibrosis; Male; Hematopoiesis, Extramedullary; Megakaryocytes; Middle Aged
PubMed: 38643827
DOI: 10.1016/j.clinme.2024.100203 -
Clinical and Translational Science Apr 2024Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with...
Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (C), area under the concentration-time curve (AUC), time to reach C, and half-life. The increase in momelotinib (23% C, 14% AUC) or M21 (30% C, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% C, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% C, 46% AUC) and increase in M21 (31% C, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (C no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% C, 16% AUC decreases) or 1'-hydroxymidazolam (14% C, 16% AUC decreases) but increased rosuvastatin C by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.
Topics: Adult; Humans; Ritonavir; Cytochrome P-450 CYP3A; Rifampin; Midazolam; ATP Binding Cassette Transporter, Subfamily G, Member 2; Rosuvastatin Calcium; Neoplasm Proteins; Drug Interactions; Membrane Transport Proteins; Benzamides; Pyrimidines
PubMed: 38634429
DOI: 10.1111/cts.13799 -
EJHaem Apr 2024Paroxysmal nocturnal hemoglobinuria (PNH) results from the loss of erythrocyte surface proteins, leading to complement activation and its spectrum of effects. We explore...
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.
PubMed: 38633120
DOI: 10.1002/jha2.892 -
Cureus Mar 2024Numerous neoplastic, viral, hematological, or metabolic conditions that affect the bone marrow might result in secondary myelofibrosis. The bone marrow aspirate results...
Numerous neoplastic, viral, hematological, or metabolic conditions that affect the bone marrow might result in secondary myelofibrosis. The bone marrow aspirate results in a dry tap and bone marrow biopsy reveals significant fibrosis replacing the normal hematopoietic cells. This is an intriguing example where a bone marrow aspirate showed a dry tap, and subsequent examination revealed a peripheral T cell lymphoma (PTCL). PTCLs are an aggressive group of non-Hodgkin's lymphoma. They often present as peripheral lymphadenopathy. The unique presentation of this case is explored in this article.
PubMed: 38618321
DOI: 10.7759/cureus.56120 -
International Journal of Molecular... Apr 2024The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera...
Conventional Cytogenetic Analysis and Array CGH + SNP Identify Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis Patients Who Are at Risk for Disease Progression.
The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (prePMF). In this study, we retrospectively reviewed the karyotypes from conventional cytogenetics (CC) and array Comparative Genomic Hybridization + Single Nucleotide Polymorphism (aCGH + SNP) in patients with ET or prePMF to determine whether the combined analysis of both methodologies can identify patients who may be at a higher risk of disease progression. We performed a comprehensive genomic review on 169 patients with a clinical diagnosis of ET (154 patients) or prePMF (15 patients). Genomic alterations detected by CC or array-CGH + SNP were detected in 36% of patients. In patients who progressed, 68% had an abnormal genomic finding by either technology. There was a shorter progression-free survival (PFS) among patients who were cytogenetically abnormal or who were cytogenetically normal but had an abnormal aCGH + SNP result. Leveraging the ability to detect submicroscopic copy number alterations and regions of copy neutral-loss of heterozygosity, we identified a higher number of patients harboring genomic abnormalities than previously reported. These results underscore the importance of genomic analysis in prognostication and provide valuable information for clinical management and treatment decisions.
Topics: Humans; Comparative Genomic Hybridization; Thrombocythemia, Essential; Polymorphism, Single Nucleotide; Primary Myelofibrosis; Retrospective Studies; Cytogenetic Analysis; Disease Progression
PubMed: 38612873
DOI: 10.3390/ijms25074061 -
Cancers Apr 2024Myelofibrosis (MF) is a myeloproliferative neoplasia arising de novo as primary myelofibrosis (PMF) or secondary to polycythemia vera or essential thrombocythemia....
Myelofibrosis (MF) is a myeloproliferative neoplasia arising de novo as primary myelofibrosis (PMF) or secondary to polycythemia vera or essential thrombocythemia. Patients experience a high symptom burden and a marked reduction in life expectancy. Despite progress in molecular understanding and treatment, the clinical and prognostic heterogeneity of MF complicates treatment decisions. The International Prognostic Scoring System (IPSS) integrates clinical factors for risk stratification in MF. This study leverages the TriNetX database with more than 64,000 MF patients to assess the impact of accessible parameters on survival and complicating events, including AML transformation, cachexia, increased systemic inflammation, thrombosis and hemorrhage. Age over 65 years correlated with increased risks of death, AML transformation, thrombosis and hemorrhage. Anemia (Hb < 10 g/dL), leukocytosis (>25 × 10/µL) and thrombocytopenia (<150 × 10/µL) reduced survival and increased risks across all assessed events. Monocytosis is associated with decreased survival, whereas eosinophilia and basophilia were linked to improved survival. Further, as proof of concept for the applicability of TriNetX for clinical scores, we devised a simplified IPSS, and confirmed its value in predicting outcomes. This comprehensive study underscores the importance of age, anemia, leukocytosis and thrombocytopenia in predicting disease trajectory and contributes to refining prognostic models, addressing the challenges posed by the disease's heterogeneity.
PubMed: 38611094
DOI: 10.3390/cancers16071416 -
Cureus Mar 2024Myeloproliferative neoplasms (MPNs) present a unique challenge in surgical management due to their inherent predisposition to both bleeding and thrombosis. MPNs are a... (Review)
Review
Myeloproliferative neoplasms (MPNs) present a unique challenge in surgical management due to their inherent predisposition to both bleeding and thrombosis. MPNs are a heterogenous group of acquired clonal conditions. The three classic MPNs are essential thrombocythemia (ET), myelofibrosis (PMF), and polycythemia vera (PV). All subtypes of MPN are associated with both thrombotic and bleeding complications. There are four risk categories for thrombosis in MPN patients: age, thrombosis history, and -2 mutation. They are further classified as very low, low, intermediate, and high risk. The genetic landscape of MPN is fascinating and complex like all myeloid disorders. Bleeding risk can be assessed through leukocytosis, thrombocytosis, acquired von Willebrand syndrome (AVWS), and a previous history of bleeding in a patient. Risk assessment and perioperative management are important aspects of improving the quality of life and preventing complications in surgeries. Preoperative management includes a risk assessment of venous thromboembolism, use of appropriate pharmacological treatment, platelet count control, and correction and cardiovascular risk factors. This review summarizes the assessment of bleeding and thrombosis risk for patients with MPNs scheduled for surgery. Furthermore, this review discusses various tools that can be used to identify MPN patients at risk of thrombosis prior to surgery.
PubMed: 38606222
DOI: 10.7759/cureus.56008