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Haematologica Dec 2022
Topics: Humans; Leukemia, Megakaryoblastic, Acute; Primary Myelofibrosis; Megakaryocytes; Chronic Disease; Leukemia
PubMed: 35295083
DOI: 10.3324/haematol.2022.280838 -
PloS One 2023Myelofibrosis is a myeloproliferative neoplasm (MPN) which typically results in reduced length and quality of life due to systemic symptoms and blood count changes...
Myelofibrosis is a myeloproliferative neoplasm (MPN) which typically results in reduced length and quality of life due to systemic symptoms and blood count changes arising from fibrotic changes in the bone marrow. While the JAK2 inhibitor ruxolitinib provides some clinical benefit, there remains a substantial unmet need for novel targeted therapies to better modify the disease process or eradicate the cells at the heart of myelofibrosis pathology. Repurposing drugs bypasses many of the hurdles present in drug development, such as toxicity and pharmacodynamic profiling. To this end we undertook a re-analysis of our pre-existing proteomic data sets to identify perturbed biochemical pathways and their associated drugs/inhibitors to potentially target the cells driving myelofibrosis. This approach identified CBL0137 as a candidate for targeting Jak2 mutation-driven malignancies. CBL0137 is a drug derived from curaxin targeting the Facilitates Chromatin Transcription (FACT) complex. It is reported to trap the FACT complex on chromatin thereby activating p53 and inhibiting NF-kB activity. We therefore assessed the activity of CBL0137 in primary patient samples and murine models of Jak2-mutated MPN and found it preferentially targets CD34+ stem and progenitor cells from myelofibrosis patients by comparison with healthy control cells. Further we investigate its mechanism of action in primary haemopoietic progenitor cells and demonstrate its ability to reduce splenomegaly and reticulocyte number in a transgenic murine model of myeloproliferative neoplasms.
Topics: Humans; Mice; Animals; Primary Myelofibrosis; Proteomics; Quality of Life; Myeloproliferative Disorders; Janus Kinase 2; Chromatin; Mutation
PubMed: 37253035
DOI: 10.1371/journal.pone.0286412 -
American Journal of Hematology Jan 2016The efficacy of hematopoietic stem cell transplantation (HSCT) is not well established in Philadelphia chromosome negative myeloproliferative neoplasms (Ph- MPNs).... (Review)
Review
The efficacy of hematopoietic stem cell transplantation (HSCT) is not well established in Philadelphia chromosome negative myeloproliferative neoplasms (Ph- MPNs). Without randomized prospective trials comparing HSCT to non-HSCT options or comparing HSCT regimens, physicians must rely on prognostic scoring systems and clinical experience when making decisions about who and when to transplant patients with Ph- MPNs. These patients are vulnerable to hepatic toxicity and graft failure after HSCT because of their increased likelihood of portal hypertension, massive splenomegaly, and extensive bone marrow fibrosis related to their disease. In this review, we aim to outline the indications and modalities of HSCT as they pertain to the Ph- MPNs and CMML based on the currently available evidence. We will further highlight the challenges of HSCT in these diseases, including but not limited to the incorporation of JAK inhibitors into HSCT for myelofibrosis.
Topics: Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Janus Kinase 2; Leukemia, Myelomonocytic, Chronic; Primary Myelofibrosis; Prognosis; Transplantation Conditioning; Transplantation, Homologous
PubMed: 26453238
DOI: 10.1002/ajh.24215 -
Journal of Thrombosis and Haemostasis :... Apr 2020The risk of thromboembolism in myelofibrosis remains incompletely understood.
BACKGROUND
The risk of thromboembolism in myelofibrosis remains incompletely understood.
OBJECTIVES
To examine the association between myelofibrosis and each of venous and arterial thromboembolism.
METHODS
A cohort of 1 469 790 adults without a diagnosis of myelofibrosis was identified on 1 January 2007, from the electronic medical records of the largest health-care provider in Israel. Participants were followed until 31 December 2016 for the occurrence of myelofibrosis. Four randomly selected controls (without myelofibrosis) were matched to each case of myelofibrosis on age, sex, religious identification, and index date. The two groups were followed from the index date until 31 December 2017 for the occurrence of venous and arterial thromboembolism.
RESULTS
The study included 642 patients with myelofibrosis and 2568 matched controls. Myelofibrosis was independently associated with increased risk of venous thromboembolism but not with arterial thromboembolism. The propensity score adjusted hazard ratios (HRs) were 6.88 (95% confidence interval [CI], 2.02-23.45) for venous thromboembolism, and 0.94 (0.49-1.77) for arterial thromboembolism. Atypical sites of venous thromboembolism occurred almost exclusively in patients with myelofibrosis (four events of Budd Chiari versus none, and two mesenteric vein thrombosis events versus one) and were more likely to occur around the time of myelofibrosis diagnosis. No significant association was found between JAK2 inhibitor treatment (ruxolitinib) and the risk of venous HR 0.97 (0.30-3.12) or arterial thromboembolism 1.68 (0.78-3.62).
CONCLUSIONS
Myelofibrosis is associated with increased risk of venous thromboembolism but not of arterial thromboembolism. Atypical sites of venous thromboembolism are more frequent in myelofibrosis and are more likely to occur shortly after diagnosis.
Topics: Adult; Cohort Studies; Humans; Israel; Primary Myelofibrosis; Retrospective Studies; Risk Factors; Venous Thromboembolism
PubMed: 32017387
DOI: 10.1111/jth.14754 -
Clinical Advances in Hematology &... Sep 2017Polycythemia vera (PV) is a Philadelphia chromosome-negative chronic myeloproliferative neoplasm that is associated with a Janus kinase 2 (JAK2) mutation in most cases.... (Review)
Review
Polycythemia vera (PV) is a Philadelphia chromosome-negative chronic myeloproliferative neoplasm that is associated with a Janus kinase 2 (JAK2) mutation in most cases. The most recent update to the World Health Organization diagnostic criteria for PV was published in 2016. These were the modifications with the greatest effect: (1) lowering the hemoglobin threshold, allowing a diagnosis of PV at 16.5 g/dL in males and at 16.0 g/dL in females and (2) introducing a hematocrit cutoff (49% in males and 48% in females). Patients with PV who are older than 60 years or have had a previous thrombotic event are considered at high risk for thrombosis. Leukocytosis and a high allele burden are additional risk factors for thrombosis and myelofibrosis, respectively. After disease has progressed to post-polycythemia vera myelofibrosis (PPV-MF), survival must be assessed according to the recently developed Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM). This model is based on age at diagnosis, a hemoglobin level below 11 g/dL, a platelet count lower than 150 × 109/L, a percentage of circulating blasts of 3% or higher, a CALR-unmutated genotype, and the presence of constitutional symptoms. Therapy is based on phlebotomy to maintain the hematocrit below 45% and (if not contraindicated) aspirin. When a cytoreductive drug is necessary, hydroxyurea or interferon can be used as first-line therapy, although the demonstration of an advantage of interferon over hydroxyurea is still pending. In patients whose disease fails to respond to hydroxyurea, ruxolitinib is a safe and effective choice.
Topics: Age Factors; Calreticulin; Female; Hematocrit; Humans; Hydroxyurea; Interferons; Janus Kinase 2; Male; Mutation; Nitriles; Polycythemia Vera; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Risk Factors; Thrombosis
PubMed: 28949941
DOI: No ID Found -
Cancer Research Mar 2022Primary myelofibrosis (PMF) is one of three myeloproliferative neoplasms (MPN) that are morphologically and molecularly inter-related, the other two being polycythemia...
Primary myelofibrosis (PMF) is one of three myeloproliferative neoplasms (MPN) that are morphologically and molecularly inter-related, the other two being polycythemia vera (PV) and essential thrombocythemia (ET). MPNs are characterized by JAK-STAT-activating JAK2, CALR, or MPL mutations that give rise to stem cell-derived clonal myeloproliferation, which is prone to leukemic and, in case of PV and ET, fibrotic transformation. Abnormal megakaryocyte proliferation is accompanied by bone marrow fibrosis and characterizes PMF, while the clinical phenotype is pathogenetically linked to ineffective hematopoiesis and aberrant cytokine expression. Among MPN-associated driver mutations, type 1-like CALR mutation has been associated with favorable prognosis in PMF, while ASXL1, SRSF2, U2AF1-Q157, EZH2, CBL, and K/NRAS mutations have been shown to be prognostically detrimental. Such information has enabled development of exclusively genetic (GIPSS) and clinically integrated (MIPSSv2) prognostic models that facilitate individualized treatment decisions. Allogeneic stem cell transplantation remains the only treatment modality in MF with the potential to prolong survival, whereas drug therapy, including JAK2 inhibitors, is directed mostly at the inflammatory component of the disease and is therefore palliative in nature. Similarly, disease-modifying activity remains elusive for currently available investigational drugs, while their additional value in symptom management awaits controlled confirmation. There is a need for genetic characterization of clinical observations followed by in vitro and in vivo preclinical studies that will hopefully identify therapies that target the malignant clone in MF to improve patient outcomes.
Topics: Humans; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential
PubMed: 34911786
DOI: 10.1158/0008-5472.CAN-21-2930 -
The New England Journal of Medicine Jun 2017
Topics: Abdomen; Aged; Hematopoiesis, Extramedullary; Humans; Kidney; Magnetic Resonance Imaging; Male; Primary Myelofibrosis; Ultrasonography
PubMed: 28636862
DOI: 10.1056/NEJMicm1700379 -
Annals of Hematology Jul 2020Myelofibrosis (MF) is a chronic myeloproliferative neoplasm which can lead to massive splenomegaly secondary to extramedullary hematopoiesis. Patients frequently exhibit... (Review)
Review
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm which can lead to massive splenomegaly secondary to extramedullary hematopoiesis. Patients frequently exhibit debilitating symptoms including pain and early satiety, in addition to cellular sequestration causing severe cytopenias. JAK 1/2 inhibitors, such as ruxolitinib and fedratinib, are the mainstay of therapy and produce significant and durable reductions in spleen volume. However, many patients are not eligible for JAK 2 inhibitor therapy or become refractory to treatment over time. Novel therapies are in development that can reduce the degree of splenomegaly for some of these patients. However, splenectomy, splenic irradiation, and partial splenic artery embolization remain valuable therapeutic options in select patients. In this review, we will discuss currently available pharmacologic therapies and describe promising drugs currently in development. We will also delve into the efficacy and safety concerns of splenectomy, splenic irradiation, and partial splenic artery embolization. Finally, we will propose a treatment algorithm to help guide clinicians in the management of symptomatic splenomegaly in patients with MF.
Topics: Embolization, Therapeutic; Humans; Primary Myelofibrosis; Protein Kinase Inhibitors; Spleen; Splenectomy; Splenic Artery; Splenomegaly
PubMed: 32417942
DOI: 10.1007/s00277-020-04069-4 -
Experimental Hematology May 2023Emperipolesis between neutrophils and megakaryocytes was first identified by transmission electron microscopy. Although rare under steady-state conditions, its frequency...
Emperipolesis between neutrophils and megakaryocytes was first identified by transmission electron microscopy. Although rare under steady-state conditions, its frequency greatly increases in myelofibrosis, the most severe of myeloproliferative neoplasms, in which it is believed to contribute to increasing the transforming growth factor (TGF)-β microenvironmental bioavailability responsible for fibrosis. To date, the challenge of performing studies by transmission electron microscopy has hampered the study of factors that drive the pathological emperipolesis observed in myelofibrosis. We established a user-friendly confocal microscopy method that detects emperipolesis by staining with CD42b, specifically expressed on megakaryocytes, coupled with antibodies that recognize the neutrophils (Ly6b or neutrophil elastase antibody). With such an approach, we first confirmed that the bone marrow from patients with myelofibrosis and from Gata1 mice, a model of myelofibrosis, contains great numbers of neutrophils and megakaryocytes in emperipolesis. Both in patients and Gata1 mice, the emperipolesed megakaryocytes were surrounded by high numbers of neutrophils, suggesting that neutrophil chemotaxis precedes the actual emperipolesis event. Because neutrophil chemotaxis is driven by CXCL1, the murine equivalent of human interleukin 8 that is expressed at high levels by malignant megakaryocytes, we tested the hypothesis that neutrophil/megakaryocyte emperipolesis could be reduced by reparixin, an inhibitor of CXCR1/CXCR2. Indeed, the treatment greatly reduced both neutrophil chemotaxis and their emperipolesis with the megakaryocytes in treated mice. Because treatment with reparixin was previously reported to reduce both TGF-β content and marrow fibrosis, these results identify neutrophil/megakaryocyte emperipolesis as the cellular interaction that links interleukin 8 to TGF-β abnormalities in the pathobiology of marrow fibrosis.
Topics: Animals; Humans; Mice; Emperipolesis; GATA1 Transcription Factor; Interleukin-8; Megakaryocytes; Neutrophils; Primary Myelofibrosis; Transforming Growth Factor beta
PubMed: 36863479
DOI: 10.1016/j.exphem.2023.02.003 -
Annals of Hematology Oct 2017Bleeding and thrombosis are long recognized complications of myelofibrosis (MF) and contribute significantly to its morbidity and mortality. However, so far, few studies... (Review)
Review
Bleeding and thrombosis are long recognized complications of myelofibrosis (MF) and contribute significantly to its morbidity and mortality. However, so far, few studies have evaluated the frequency of these events, their characteristics, and their prognostic impact. Based on these studies, thrombotic events in MF are about as common as in essential thrombocytemia (ET) but less common than in polycythemia vera (PV), while bleeding events are relatively more common in MF than in ET or PV. The emergence of the concept of prefibrotic primary MF (PMF), which is associated with a higher frequency of thrombohemorrhagic complications than ET, and the growing evidence that prefibrotic PMF may also have a different thrombotic and bleeding risk profiles than fibrotic (overt) PMF have emphasized the need for a reappraisal of the risk of thrombosis and hemorrhage in patients with MF. In this review, we discuss the frequency of thrombosis and bleeding in patients with MF, including prefibrotic PMF and their established and potential risk factors.
Topics: Hemorrhage; Humans; Polycythemia Vera; Primary Myelofibrosis; Risk Factors; Thrombocythemia, Essential; Thrombosis
PubMed: 28808761
DOI: 10.1007/s00277-017-3099-2