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Journal of Translational Medicine Oct 2023Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not... (Review)
Review
Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not well established except in its primary form. The present review consolidates current understanding of marrow fibrosis. We searched PubMed without time restriction using key words: bone marrow and fibrosis as the main stem against the terms: growth factors, cytokines and chemokines, morphology, megakaryocytes and platelets, myeloproliferative disorders, myelodysplastic syndrome, collagen biosynthesis, mesenchymal stem cells, vitamins and minerals and hormones, and mechanism of tissue fibrosis. Tissue marrow fibrosis-related papers were short listed and analysed for the review. It emerged that bone marrow fibrosis is the outcome of complex interactions between growth factors, cytokines, chemokines and hormones together with their facilitators and inhibitors. Fibrogenesis is initiated by mobilisation of special immunophenotypic subsets of mesenchymal stem cells in the marrow that transform into fibroblasts. Fibrogenic stimuli may arise from neoplastic haemopoietic or non-hematopoietic cells, as well as immune cells involved in infections and inflammatory conditions. Autoimmunity is involved in a small subset of patients with marrow fibrosis. Megakaryocytes and platelets are either directly involved or are important intermediaries in stimulating mesenchymal stem cells. MMPs, TIMPs, TGF-β, PDGRF, and basic FGF and CRCXL4 chemokines are involved in these processes. Genetic and epigenetic changes underlie many of these conditions.
Topics: Humans; Bone Marrow; Primary Myelofibrosis; Cytokines; Fibrosis; Chemokines; Hormones
PubMed: 37814319
DOI: 10.1186/s12967-023-04393-z -
Blood Apr 2024
Topics: Humans; Primary Myelofibrosis; Myeloproliferative Disorders; Mutation; Carrier Proteins; Nuclear Proteins
PubMed: 38573606
DOI: 10.1182/blood.2023023757 -
Cancers Jul 2023Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic...
Clinical Characteristics and Outcomes of Patients with Primary and Secondary Myelofibrosis According to the Genomic Classification Using Targeted Next-Generation Sequencing.
Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic classification of MF considering whether it is primary or secondary. One-hundred seventy-five patients, 81 with primary MF (PMF) and 94 with secondary MF (SMF) were hierarchically allocated into eight molecular groups. We found that disruption/aneuploidy ( = 16, 9%) was more frequent (12% versus 6%) and showed higher allele burden (57% versus 15%, = 0.01) in SMF than in PMF, and was associated with shorter survival (median 3.5 years). Mutations in chromatin/spliceosome genes ( = 72, 41%) represented the most frequent genomic group in PMF. Homozygous mutation ( = 40, 23%) was enriched with old patients with SMF after long-standing polycythemia vera, whereas MF with heterozygous mutation ( = 22, 13%) was similarly distributed among PMF and SMF. MF with mutation ( = 19, 11%) predominated in post-essential thrombocythemia MF. The remaining genomic groups were infrequent. disruption, chromatin/spliceosome mutation, and homozygous mutation were associated with significantly shorter survival and higher risk of progression. In conclusion, genomic classification reveals different pathogenic pathways between PMF and SMF and provides relevant information regarding disease phenotype and outcomes.
PubMed: 37568719
DOI: 10.3390/cancers15153904 -
The Lancet. Haematology May 2024Myelofibrosis is a myeloid neoplasm characterised by the presence of JAK2, CALR, or MPL mutations (with a 90% mutation frequency) and trilineage myeloid proliferation...
Myelofibrosis is a myeloid neoplasm characterised by the presence of JAK2, CALR, or MPL mutations (with a 90% mutation frequency) and trilineage myeloid proliferation with prominent megakaryocyte atypia. People with myelofibrosis have a lower survival rate and poorer quality of life than healthy individuals. Therapy for myelofibrosis uses Janus kinase inhibitors, which reduce splenomegaly and alleviate symptoms. Regulatory approvals for Janus kinase inhibitors have focused on this dual endpoint. In this Viewpoint, we discuss the validity of using spleen reduction as a surrogate endpoint for the disease-modifying activity of candidate drugs for myelofibrosis. We suggest alternative endpoints addressing unmet patient needs, including progression-free survival and overall survival. Moreover, we highlight the importance of selecting a core set of crucial outcomes with which we can individualise clinical decision making and standardise reporting of clinical trials results. We propose selecting patient-reported outcomes and anaemia response. We also suggest integrating economic considerations in the process of evaluating new drugs for myelofibrosis.
Topics: Humans; Clinical Trials as Topic; Endpoint Determination; Janus Kinase Inhibitors; Primary Myelofibrosis; Quality of Life
PubMed: 38604205
DOI: 10.1016/S2352-3026(24)00067-X -
Hematology. American Society of... Dec 2023Myeloproliferative neoplasms (MPNs) are characterized by clonal myeloproliferation in 1 or more of the hematopoietic stem cell lineages. Primary myelofibrosis (MF),...
Myeloproliferative neoplasms (MPNs) are characterized by clonal myeloproliferation in 1 or more of the hematopoietic stem cell lineages. Primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF have the worst prognosis and are characterized by the presence of cytokine-mediated symptom complex, splenomegaly, progressive marrow failure, and clonal instability, leading to leukemic transformation. The key therapeutic aims encompass the management of symptoms, splenomegaly, and anemia and the improvement of survivals. These therapeutic aims have evolved with the availability of Jak inhibitors and novel agents, making disease modification potentially achievable. Novel agents may potentially target MPN stem cells, epigenetic alterations, signaling pathways, and apoptotic pathways. In this case-based review, we outline our approach to the management of MF and discuss the therapeutic landscape of MF, highlighting the utility of Jak inhibitors and novel Jak inhibitor-based combinations.
Topics: Humans; Primary Myelofibrosis; Splenomegaly; Janus Kinase Inhibitors; Thrombocythemia, Essential; Myeloproliferative Disorders
PubMed: 38066870
DOI: 10.1182/hematology.2023000452 -
HemaSphere Nov 2023Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients'...
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients' quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.
PubMed: 37901848
DOI: 10.1097/HS9.0000000000000966 -
Immunological Medicine Sep 2023JAK inhibitors are important therapeutic options for hematological disorders, especially myeloproliferative neoplasms. Ruxolitinib, the first JAK inhibitor approved for... (Review)
Review
JAK inhibitors are important therapeutic options for hematological disorders, especially myeloproliferative neoplasms. Ruxolitinib, the first JAK inhibitor approved for clinical use, improves splenomegaly and ameliorates constitutional symptoms in both myelofibrosis and polycythemia vera patients. Ruxolitinib is also useful for controlling hematocrit levels in polycythemia vera patients who were inadequately controlled by conventional therapies. Furthermore, pretransplantation use of ruxolitinib may improve the outcome of allo-hematopoietic stem cell transplantation in myelofibrosis. In contrast to these clinical merits, evidence of the disease-modifying action of ruxolitinib, i.e., reduction of malignant clones or improvement of bone marrow pathological findings, is limited, and many myelofibrosis patients discontinued ruxolitinib due to adverse events or disease progression. To overcome these limitations of ruxolitinib, several new types of JAK inhibitors have been developed. Among them, fedratinib was proven to provide clinical merits even in patients who were resistant or intolerant to ruxolitinib. Pacritinib and momelotinib have shown merits for myelofibrosis patients with thrombocytopenia or anemia, respectively. In addition to treatment for myeloproliferative neoplasms, recent studies have demonstrated that JAK inhibitors are novel and attractive therapeutic options for corticosteroid-refractory acute as well as chronic graft versus host disease.
Topics: Humans; Polycythemia Vera; Janus Kinase Inhibitors; Primary Myelofibrosis; Janus Kinase 2; Protein Kinase Inhibitors; Myeloproliferative Disorders
PubMed: 36305377
DOI: 10.1080/25785826.2022.2139317 -
European Journal of Haematology Nov 2023Autoimmune myelofibrosis (AIMF) is a rare cause of bone marrow fibrosis (BMF) occurring in the presence or absence of a defined autoimmune disease (secondary or primary... (Review)
Review
BACKGROUND AND OBJECTIVES
Autoimmune myelofibrosis (AIMF) is a rare cause of bone marrow fibrosis (BMF) occurring in the presence or absence of a defined autoimmune disease (secondary or primary AIMF, sAIMF/pAIMF, respectively). Unlike primary myelofibrosis (PMF), AIMF responds well to immunosuppressive therapy with a benign clinical course. Diagnostic criteria for AIMF in opposition to PMF have been lacking, though recent work has helped better characterise molecular and pathological features of AIMF, improving diagnostic precision.
METHODS
Using a modern clinical and pathophysiological understanding of AIMF, we apply scoping review methodology and rigorous case-criteria to retrospectively analyse the case literature. We examine its patient-population, describing patient-associated factors, presentation, bone marrow pathology, genetics, treatment and outcomes.
RESULTS
Fifty-five studies were identified, describing 139 AIMF patients. Patients were mostly young females (~4:1 ratio female:male, median age 40.8 years) and typically presented with cytopenias. Splenomegaly was rare. sAIMF was more common than pAIMF (~3:1 ratio), and most cases responded well to immunosuppressive therapy.
CONCLUSIONS
Our results strengthen the emerging picture of AIMF's patient population, natural history and response to treatment. Further work should continue to use reproducible diagnostic criteria, and explore AIMF's pathophysiology, response to different therapies, and sequelae over larger timescales, as well as differences between pAIMF, sAIMF and PMF.
Topics: Humans; Male; Female; Adult; Primary Myelofibrosis; Retrospective Studies; Bone Marrow; Autoimmune Diseases; Immunosuppression Therapy
PubMed: 37515415
DOI: 10.1111/ejh.14064 -
Clinical and Experimental Medicine Dec 2023Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by the proliferation of one or more... (Review)
Review
Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by the proliferation of one or more hematopoietic lineage(s). The classical Philadelphia-chromosome (Ph)-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The Asian Myeloid Working Group (AMWG) comprises representatives from fifteen Asian centers experienced in the management of MPN. This consensus from the AMWG aims to review the current evidence in the risk stratification and treatment of Ph-negative MPN, to identify management gaps for future improvement, and to offer pragmatic approaches for treatment commensurate with different levels of resources, drug availabilities and reimbursement policies in its constituent regions. The management of MPN should be patient-specific and based on accurate diagnostic and prognostic tools. In patients with PV, ET and early/prefibrotic PMF, symptoms and risk stratification will guide the need for early cytoreduction. In younger patients requiring cytoreduction and in those experiencing resistance or intolerance to hydroxyurea, recombinant interferon-α preparations (pegylated interferon-α 2A or ropeginterferon-α 2b) should be considered. In myelofibrosis, continuous risk assessment and symptom burden assessment are essential in guiding treatment selection. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in MF should always be based on accurate risk stratification for disease-risk and post-HSCT outcome. Management of classical Ph-negative MPN entails accurate diagnosis, cytogenetic and molecular evaluation, risk stratification, and treatment strategies that are outcome-oriented (curative, disease modification, improvement of quality-of-life).
Topics: Humans; Philadelphia Chromosome; Consensus; Myeloproliferative Disorders; Polycythemia Vera; Thrombocythemia, Essential; Interferon-alpha
PubMed: 37747591
DOI: 10.1007/s10238-023-01189-9 -
Haematologica Feb 2024BCR::ABL1 negative myeloproliferative neoplasms (MPNs) form a distinct group of hematologic malignancies characterized by sustained proliferation of cells from multiple...
BCR::ABL1 negative myeloproliferative neoplasms (MPNs) form a distinct group of hematologic malignancies characterized by sustained proliferation of cells from multiple myeloid lineages. With a median survival of 16-35 months in patients with high-risk disease, primary myelofibrosis (PMF) is considered the most aggressive entity amongst all BCR::ABL1 MPNs. Additionally, a significant subset of patients evolves into secondary acute myeloid leukemia (AML) which has an even poorer prognosis compared to de novo AML. As the exact mechanisms of disease development and progression remain to be elucidated, current therapeutic approaches fail to prevent disease progression or transformation into secondary AML. As each MPN entity is characterized by sustained activation of various immune cells and raised cytokine concentrations within bone marrow and peripheral blood, MPNs may be considered as typical inflammation-related malignancies. However, the exact role and consequences of increased cytokine concentrations within bone marrow and peripheral blood plasma are currently incompletely established. Upregulated cytokines can stimulate cellular proliferation or contribute to the development of an inflammation-related bone marrow niche resulting in genotoxicity and thereby supporting mutagenesis. The neutrophil chemoattractant CXCL8 is of specific interest as its concentration is increased within peripheral blood and bone marrow plasma of patients with PMF. Increased concentration of CXCL8 negatively correlates with overall survival. Furthermore, blockage of the CXCR1/2 axis appears to be able to reduce bone marrow fibrosis and megakaryocyte dysmorphia in murine models. Within this review, we summarize available evidence on the role of the CXCL8-CXCR1/2 axis within the pathogenesis of PMF and discuss potential therapeutic modalities targeting either CXCL8 or its cognate receptors CXCR1/2.
PubMed: 38426279
DOI: 10.3324/haematol.2023.284921