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Life (Basel, Switzerland) Apr 2024To investigate the prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), platelet count and their ratios, neutrophil-lymphocyte ratio (NLR) and...
AIM
To investigate the prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), platelet count and their ratios, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), to thrombotic risk in patients with prefibrotic and overt fibrotic myelofibrosis (MF).
METHODS
We retrospectively analyzed a cohort of 256 patients with prefibrotic (85 patients) and overt fibrotic MF (171 patients) treated in six Croatian hematological centers.
RESULTS
Prefibrotic compared to overt fibrotic MF patients presented with significantly higher ALC, platelet count and PLR, and experienced longer time to thrombosis (TTT). Among prefibrotic patients, ANC > 8.33 × 10/L (HR 13.08, = 0.036), ALC > 2.58 × 10/L (HR 20.63, = 0.049) and platelet count > 752 × 10/L (HR 10.5, = 0.043) remained independently associated with shorter TTT. Among overt fibrotic patients, ANC > 8.8 × 10/L (HR 4.49, = 0.004), ALC ≤ 1.43 × 10/L (HR 4.15, = 0.003), platelet count ≤ 385 × 10/L (HR 4.68, = 0.004) and chronic kidney disease (HR 9.07, < 0.001) remained independently associated with shorter TTT.
CONCLUSIONS
Prognostic properties of ANC, ALC and platelet count are mutually independent and exceed those of NLR and PLR regarding thrombotic risk stratification. ALC and platelet count associate in opposite directions with thrombotic risk in prefibrotic and overt fibrotic MF patients.
PubMed: 38672793
DOI: 10.3390/life14040523 -
Antioxidants (Basel, Switzerland) Apr 2024To date, little is known concerning the circulating levels of biochemically relevant metabolites (antioxidants, oxidative/nitrosative stress biomarkers, purines, and...
Targeted Metabolomics Highlights Dramatic Antioxidant Depletion, Increased Oxidative/Nitrosative Stress and Altered Purine and Pyrimidine Concentrations in Serum of Primary Myelofibrosis Patients.
To date, little is known concerning the circulating levels of biochemically relevant metabolites (antioxidants, oxidative/nitrosative stress biomarkers, purines, and pyrimidines) in patients with primary myelofibrosis (PMF), a rare form of myeloproliferative tumor causing a dramatic decrease in erythropoiesis and angiogenesis. In this study, using a targeted metabolomic approach, serum samples of 22 PMF patients and of 22 control healthy donors were analyzed to quantify the circulating concentrations of hypoxanthine, xanthine, uric acid (as representative purines), uracil, β-pseudouridine, uridine (as representative pyrimidines), reduced glutathione (GSH), ascorbic acid (as two of the main water-soluble antioxidants), malondialdehyde, nitrite, nitrate (as oxidative/nitrosative stress biomarkers) and creatinine, using well-established HPLC method for their determination. Results showed that PMF patients have dramatic depletions of both ascorbic acid and GSH (37.3- and 3.81-times lower circulating concentrations, respectively, than those recorded in healthy controls, < 0.0001), accompanied by significant increases in malondialdehyde (MDA) and nitrite + nitrate (4.73- and 1.66-times higher circulating concentrations, respectively, than those recorded in healthy controls, < 0.0001). Additionally, PMF patients have remarkable alterations of circulating purines, pyrimidines, and creatinine, suggesting potential mitochondrial dysfunctions causing energy metabolism imbalance and consequent increases in these cell energy-related compounds. Overall, these results, besides evidencing previously unknown serum metabolic alterations in PMF patients, suggest that the determination of serum levels of the aforementioned compounds may be useful to evaluate PMF patients on hospital admission for adjunctive therapies aimed at recovering their correct antioxidant status, as well as to monitor patients' status and potential pharmacological treatments.
PubMed: 38671937
DOI: 10.3390/antiox13040490 -
Polish Archives of Internal Medicine Jun 2024
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Polycythemia Vera; Primary Myelofibrosis; Male; Disease Progression; Aged; Myelodysplastic Syndromes; Middle Aged
PubMed: 38656083
DOI: 10.20452/pamw.16735 -
Annals of Hematology Jun 2024
Triple a score (AAA: age, absolute neutrophil count and absolute lymphocyte count) and its prognostic utility in patients with overt fibrotic and prefibrotic myelofibrosis.
Topics: Humans; Primary Myelofibrosis; Neutrophils; Lymphocyte Count; Male; Female; Aged; Middle Aged; Leukocyte Count; Prognosis; Age Factors; Aged, 80 and over; Adult
PubMed: 38652241
DOI: 10.1007/s00277-024-05751-7 -
Cytometry. Part B, Clinical Cytometry Apr 2024Thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), prefibrotic/early (pre-PMF), and overt fibrotic PMF (overt PMF) are classical...
Thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), prefibrotic/early (pre-PMF), and overt fibrotic PMF (overt PMF) are classical Philadelphia-Negative (Ph-negative) myeloproliferative neoplasms (MPNs). Differentiating between these types based on morphology and molecular markers is challenging. This study aims to clarify the application of flow cytometry in the diagnosis and differential diagnosis of classical MPNs. This study retrospectively analyzed the immunophenotypes, clinical characteristics, and laboratory findings of 211 Ph-negative MPN patients, including ET, PV, pre-PMF, overt PMF, and 47 controls. Compared to ET and PV, PMF differed in white blood cells, hemoglobin, blast cells in the peripheral blood, abnormal karyotype, and WT1 gene expression. PMF also differed from controls in CD34 cells, granulocyte phenotype, monocyte phenotype, percentage of plasma cells, and dendritic cells. Notably, the PMF group had a significantly lower plasma cell percentage compared with other groups. A lasso and random forest model select five variables (CD34CD19cells and CD34CD38 cells on CD34cells, CD13CD11b cells in granulocytes, CD38CD19plasma, and CD123HLA-DRbasophils), which identify PMF with a sensitivity and specificity of 90%. Simultaneously, a classification and regression tree model was constructed using the percentage of CD34CD38 on CD34 cells and platelet counts to distinguish between ET and pre-PMF, with accuracies of 94.3% and 83.9%, respectively. Flow immunophenotyping aids in diagnosing PMF and differentiating between ET and PV. It also helps distinguish pre-PMF from ET and guides treatment decisions.
PubMed: 38647185
DOI: 10.1002/cyto.b.22173 -
American Journal of Hematology Jul 2024Emerging evidence shows the crucial role of inflammation (particularly NF-κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising...
Emerging evidence shows the crucial role of inflammation (particularly NF-κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising therapeutic target. Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias. Since recent studies have highlighted the role of miR-146a, a negative regulator of the NF-κB pathway, in the pathogenesis of MF; here we used miR-146a (KO) mice, a MF-like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK/STAT and/or NF-κB pathways may reverse the myelofibrotic phenotype of these mice. Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF-κB inhibitor via IKKα/β, BMS-345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib. Although all treatments decreased spleen size and partially recovered its architecture, only NF-κB inhibition, either using BMS-345541 (alone or in combination) or pacritinib, resulted in a reduction of extramedullary hematopoiesis, bone marrow (BM) fibrosis and osteosclerosis, along with an attenuation of the exacerbated inflammatory state (via IL-1β and TNFα). However, although dual inhibitor improved anemia and reversed thrombocytopenia, the combined therapy worsened anemia by inducing BM hypoplasia. Both therapeutic options reduced NF-κB and JAK/STAT signaling in a context of JAK2V617F-driven clonal hematopoiesis. Additionally, combined treatment reduced both COL1A1 and IL-6 production in an in vitro model mimicking JAK2-driven fibrosis. In conclusion, NF-κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.
Topics: Animals; Primary Myelofibrosis; MicroRNAs; Mice; NF-kappa B; Nitriles; Pyrimidines; Pyrazoles; Mice, Knockout; Signal Transduction; Disease Models, Animal; Hematopoiesis, Extramedullary
PubMed: 38646919
DOI: 10.1002/ajh.27322 -
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 -
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 -
Bone Marrow Transplantation Apr 2024This retrospective study evaluated 35 children (median age 5.2 years; range 0.4-18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary...
This retrospective study evaluated 35 children (median age 5.2 years; range 0.4-18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II-IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3-41.1) vs 58.8% (31-78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1-32.8), relapse incidence was 15.9% (5.6-30.9), progression-free survival (PFS) was 66.1% (47-79.7), GvHD-free relapse-free survival was 50% (30.6-66.7), and overall survival (OS) was 71.1% (51.4-84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3-96.1) vs 50.8% (26.3-71), p = 0.03, and 90.9% (50.8-98.7) vs 54% (28.1-74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3-53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies.
PubMed: 38627449
DOI: 10.1038/s41409-024-02286-3 -
Hematology (Amsterdam, Netherlands) Dec 2024Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that...
OBJECTIVES
Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study.
METHODS
Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma.
RESULTS
Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, = 8; essential thrombocythemia, = 14; and primary myelofibrosis, = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed ( = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy.
CONCLUSION
Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.
Topics: Humans; Polycythemia Vera; Thrombocythemia, Essential; Retrospective Studies; Multiple Myeloma; Japan; Myeloproliferative Disorders; Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell
PubMed: 38626148
DOI: 10.1080/16078454.2024.2340149