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Expert Opinion on Pharmacotherapy Apr 2024Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the... (Review)
Review
INTRODUCTION
Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. However, their myelosuppressive effect coupled with the persistence, and even worsening anemia remains a significant challenge, leading usually to treatment discontinuation.
AREAS COVERED
This review focuses on Momelotinib (MMB), a unique JAK inhibitor that has shown promise in MF treatment, particularly in improving anemia. MMB inhibits type 1 kinase activin A receptor or activin receptor-like kinase-2 (ACVR1/ALK2), with consequent rebalancing of the SMAD pathways and reduced transcription of hepcidin. Moreover, it seems that MMB could reduce the serum levels of several inflammatory cytokines responsible for anemia. Clinical trials have demonstrated MMB's efficacy in reducing spleen size, alleviating symptoms, and improving anemia, with a favorable safety profile compared to other JAK inhibitors, both in treatment-naïve and in pre-treated patients.
EXPERT OPINION
Due to its mechanism of action, MMB represents a valuable therapeutic option in MF, addressing the clinical challenge of anemia and potentially improving outcomes for patients with hematologic malignancies. Ongoing research explores MMB's potential in acute myeloid leukemia and combination therapies.
Topics: Humans; Primary Myelofibrosis; Pyrimidines; Animals; Benzamides; Janus Kinase Inhibitors; Anemia; Bridged-Ring Compounds
PubMed: 38623844
DOI: 10.1080/14656566.2024.2343780 -
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 -
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 -
Virchows Archiv : An International... May 2024The classical BCR::ABL1-negative myeloproliferative neoplasms (MPN) form a group of bone marrow (BM) diseases with the potential to progress to acute myeloid leukemia or...
The classical BCR::ABL1-negative myeloproliferative neoplasms (MPN) form a group of bone marrow (BM) diseases with the potential to progress to acute myeloid leukemia or develop marrow fibrosis and subsequent BM failure. The mechanism by which BM fibrosis develops and the factors that drive stromal activation and fibrosis are not well understood. Cellular Communication Network 2 (CCN2), also known as CTGF (Connective Tissue Growth Factor), is a profibrotic matricellular protein functioning as an important driver and biomarker of fibrosis in a wide range of diseases outside the marrow. CCN2 can promote fibrosis directly or by acting as a factor downstream of TGF-β, the latter already known to contribute to myelofibrosis in MPN.To study the possible involvement of CCN2 in BM fibrosis in MPN, we assessed CCN2 protein expression by immunohistochemistry in 75 BM biopsies (55 × MPN and 20 × normal controls). We found variable expression of CCN2 in megakaryocytes with significant overexpression in a subgroup of 7 (13%) MPN cases; 4 of them (3 × essential thrombocytemia and 1 × prefibrotic primary myelofibrosis) showed no fibrosis (MF-0), 2 (1 × post-polycythemic myelofibrosis and 1 × primary myelofibrosis) showed moderate fibrosis (MF-2), and 1 (primary myelofibrosis) severe fibrosis (MF-3). Remarkably, CCN2 expression did not correlate with fibrosis or other disease parameters such as platelet count or thrombovascular events, neither in this subgroup nor in the whole study group. This suggests that in BM of MPN patients other, CCN2-independent pathways (such as noncanonical TGF-β signaling) may be more important for the development of fibrosis.
Topics: Humans; Connective Tissue Growth Factor; Transforming Growth Factor beta; Primary Myelofibrosis; Signal Transduction; Middle Aged; Male; Female; Aged; Myeloproliferative Disorders; Adult; Bone Marrow; Aged, 80 and over; Immunohistochemistry; Fibrosis
PubMed: 38602559
DOI: 10.1007/s00428-024-03799-4 -
Frontiers in Cell and Developmental... 2024Myeloproliferative neoplasms (MPNs) are subdivided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. translocation is... (Review)
Review
Myeloproliferative neoplasms (MPNs) are subdivided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. translocation is essential for the development and diagnosis of CML; on the other hand, the majority of Ph-negative MPNs are characterized by generally mutually exclusive mutations of Janus kinase 2 (), calreticulin (), or thrombopoietin receptor/myeloproliferative leukemia (). mutations have been described essentially in and wild-type essential thrombocythemia and primary myelofibrosis. Rarely coexisting and mutations have been found in Ph-negative MPNs. translocation and mutations were initially considered mutually exclusive genomic events, but a discrete number of cases with the combination of these genetic alterations have been reported. The presence of translocation with a coexisting mutation is even more uncommon. Herein, starting from a routinely diagnosed case of -mutated primary myelofibrosis subsequently acquiring translocation, we performed a comprehensive review of the literature, discussing the clinicopathologic and molecular features, as well as the outcome and treatment of cases with and co-occurrence.
PubMed: 38596359
DOI: 10.3389/fcell.2024.1391078 -
Medicine Apr 2024Primary myelofibrosis is a subtype of myeloproliferative neoplasm that leads to bone marrow fibrosis. Historically, the only curative option for primary myelofibrosis... (Review)
Review
RATIONALE
Primary myelofibrosis is a subtype of myeloproliferative neoplasm that leads to bone marrow fibrosis. Historically, the only curative option for primary myelofibrosis was allogeneic hematopoietic stem cell transplant. Ruxolitinib, a Janus kinase inhibitor, is now used for the treatment of primary myelofibrosis and polycythemia vera. It effectively improves symptoms related to splenomegaly and anemia. However, its association with the development of opportunistic infections has been observed in clinical studies and practical application.
PATIENT CONCERNS
A 64-year-old female with primary myelofibrosis and chronic hepatitis B infection who received ruxolitinib treatment. She was admitted for spiking fever and altered consciousness.
DIAGNOSIS
Tuberculosis meningitis was suspected but cerebrospinal fluid can't identify any pathogens. An abdominal computed tomography scan revealed a left psoas abscess and an enlarged spleen. A computed tomography-guided pus drainage procedure was performed, showing a strong positive acid-fast stain and a positive Mycobacterium tuberculosis polymerase chain reaction result.
INTERVENTIONS
antituberculosis medications were administered. The patient developed a psoas muscle abscess caused by tuberculosis and multiple dermatomes of herpes zoster during antituberculosis treatment.
OUTCOMES
The patient was ultimately discharged after 6 weeks of treatment without apparent neurological sequelae.
LESSONS
This case underscores the importance of clinicians evaluating latent infections and ensuring full vaccination prior to initiating ruxolitinib-related treatment for primary myelofibrosis.
Topics: Female; Humans; Middle Aged; Nitriles; Primary Myelofibrosis; Psoas Abscess; Psoas Muscles; Pyrazoles; Pyrimidines; Splenomegaly; Tuberculosis
PubMed: 38579059
DOI: 10.1097/MD.0000000000037653 -
Journal of Medical Case Reports Apr 2024A long-term ruxolitinib-treated patient with primary myelofibrosis, who was co-infected with aspergillosis infection during a short period, developed acute invasive...
INTRODUCTION
A long-term ruxolitinib-treated patient with primary myelofibrosis, who was co-infected with aspergillosis infection during a short period, developed acute invasive fungal sinusitis with consequent orbit apex syndrome. This may be the first reported case in the world. This is a 75-year-old Chinese man; the patient was admitted with 2-month history of headache accompanied by numbness and 8-day history of vision loss. The preliminary clinical diagnoses were suspected acute invasive fungal sinusitis or adenoid cystic carcinoma. We performed endoscopic debridement and antifungal therapy. About 90 days after surgery, magnetic resonance imaging revealed no recurrence of pathological tissue.
CONCLUSION
One of the bases for the occurrence of invasive fungal sinusitis may be the patient's long-term use of ruxolitinib for essential thrombocythemia. Some patients with invasive fungal sinuses have atypical nasal symptoms and are referred to the corresponding departments with eye and headache as the first symptoms. It is suggested that enhanced magnetic resonance imaging should be performed at an early stage. Surgical treatment in combination with antifungal and enhanced immunotherapy can effectively prevent the spread of infection and reduce the risk of death.
Topics: Aged; Humans; Male; Antifungal Agents; Headache; Nitriles; Pyrazoles; Pyrimidines; Sinusitis
PubMed: 38576050
DOI: 10.1186/s13256-024-04486-3 -
Blood Apr 2024
Topics: Humans; Primary Myelofibrosis; Myeloproliferative Disorders; Mutation; Carrier Proteins; Nuclear Proteins
PubMed: 38573606
DOI: 10.1182/blood.2023023757 -
Indian Journal of Pathology &... Mar 2024
PubMed: 38563691
DOI: 10.4103/ijpm.ijpm_365_23