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Blood Cancer Journal Jul 2023
Topics: Humans; Primary Myelofibrosis; Thrombocythemia, Essential; Motivation; Thrombosis; Bone Marrow
PubMed: 37507408
DOI: 10.1038/s41408-023-00887-7 -
Journal of Clinical Oncology : Official... Jan 2020
Topics: Healthcare Disparities; Hispanic or Latino; Humans; Male; Middle Aged; Military Medicine; Narration; Pancytopenia; Primary Myelofibrosis; Stem Cell Transplantation
PubMed: 31664879
DOI: 10.1200/JCO.19.01497 -
Hematology. American Society of... Dec 2022The application of genomic techniques, including cytogenetics and DNA sequencing, to decipher the molecular landscape of patients with myeloproliferative neoplasms...
The application of genomic techniques, including cytogenetics and DNA sequencing, to decipher the molecular landscape of patients with myeloproliferative neoplasms (MPNs) has radically modified diagnostic approach and management through improved risk stratification. Three driver mutated genes (JAK2, MPL, CALR) are variably harbored by >80% of patients and associated with clinical characteristics, as well as major disease-related complications and different survival outcomes. Therefore, JAK2 V617F mutation is included in the revised International Prognosis Score of Thrombosis for Essential Thrombocythemia score for prediction of thrombosis in patients with essential thrombocythemia and prefibrotic primary myelofibrosis, while a CALR type 1 mutated genotype constitutes a favorable variable for survival in patients with myelofibrosis (MF). Novel, integrated clinical and cytogenetic/mutation scores (Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients with Primary Myelofibrosis [MIPSS70/v2], genetically inspired prognostic scoring system [GIPSS], Myelofibrosis Secondary to PV and ET- Prognostic Model [MYSEC-PM]) have been devised that guide selection of stem cell transplantation candidates with MF or help predict the risk associated with the transplant procedure (Myelofibrosis Transplant Scoring System), with greater performance compared with conventional scores based on hematologic and clinical variables only. On the other hand, several clinical needs remain unmet despite the great amount of molecular information available nowadays. These include the prediction of evolution to acute leukemia in a clinically actionable time frame, the identification of patients most likely to derive durable benefits from target agents, in primis JAK inhibitors, and, conversely, the significance of molecular responses that develop in patients receiving interferon or some novel agents. Here, we discuss briefly the significance and the role of genomic analysis for prognostication in patients with MPNs from a clinician's point of view, with the intent to provide how-to-use hints.
Topics: Humans; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Primary Myelofibrosis; Prognosis; Thrombocythemia, Essential
PubMed: 36485130
DOI: 10.1182/hematology.2022000339 -
Expert Review of Hematology Jan 2020: Recent advances in the prognostic scheme and treatment of primary and secondary myelofibrosis (MF) have resulted in an overwhelming amount of clinical information to...
: Recent advances in the prognostic scheme and treatment of primary and secondary myelofibrosis (MF) have resulted in an overwhelming amount of clinical information to assimilate. The authors believe a comprehensive review that summarizes the most recent published literature, could serve as guidelines for the practicing hematologist.: The authors provide a summary of landmark articles regarding epidemiology, symptoms, and pathogenesis of disease. The authors conducted a systematic literature review to answer questions regarding differences between primary myelofibrosis (PMF) and secondary myelofibrosis (SMF), appropriate use and selection of the current risk-stratification models, early versus late treatment of MF and current practices in allogeneic hematopoietic stem cell transplantation (allo-HCT) for MF. The authors conclude the article with their clinical opinion based on their experience and literature review. The purpose of this article is to identify current practices, address any variation, identify and investigate conflicting results and produce statements to guide decision-making.: In this section, the authors advocate for and provide examples of a standardized way of incorporating future discoveries in the pathogenesis and risk-stratification models of MF. They also discuss the importance of using only one risk-stratification model for PMF and one for SMF and their reasoning for early instead of late treatment of MF.
Topics: Allografts; Clinical Decision-Making; Hematopoietic Stem Cell Transplantation; Humans; Models, Biological; Practice Guidelines as Topic; Primary Myelofibrosis; Risk Assessment; Risk Factors
PubMed: 31709843
DOI: 10.1080/17474086.2020.1691519 -
Blood Advances Sep 2023Janus kinase inhibitors (JAKis) ruxolitinib, fedratinib, and pacritinib are the current standard of care in symptomatic myelofibrosis (MF). However, progressive disease...
Janus kinase inhibitors (JAKis) ruxolitinib, fedratinib, and pacritinib are the current standard of care in symptomatic myelofibrosis (MF). However, progressive disease and toxicities frequently lead to JAKi discontinuation. Preclinical data indicate that combining JAK and bromodomain and extraterminal (BET) domain inhibition leads to overlapping effects in MF. Pelabresib (CPI-0610), an oral, small-molecule BET1,2 inhibitor (BETi), in combination with ruxolitinib showed improvements in spleen volume reduction (SVR35) and total symptom score reduction (TSS50) from baseline in the phase 2 MANIFEST study (NCT02158858) in patients with MF. Given the absence of a head-to-head clinical comparison between JAKi monotherapy and JAKi with BETi combination therapy, we performed an unanchored matching-adjusted indirect comparison analysis to adjust for differences between studies and allow for the comparison of SVR35, TSS50, and TSS measured at several timepoints in arm 3 of MANIFEST (pelabresib with ruxolitinib in JAKi treatment-naive patients with MF), with data from the following JAKi monotherapy studies in JAKi treatment-naive patients: COMFORT-I and COMFORT-II (ruxolitinib), SIMPLIFY-1 (ruxolitinib and momelotinib), and JAKARTA (fedratinib). Response rate ratios >1 were observed for pelabresib with ruxolitinib vs all comparators for SVR35 and TSS50 at week 24. Improvements in TSS were observed as early as week 12 and were durable. These results indicate that pelabresib with ruxolitinib may have a potentially higher efficacy than JAKi monotherapy in JAKi treatment-naive MF.
Topics: Humans; Primary Myelofibrosis; Pyrimidines; Nitriles
PubMed: 37530627
DOI: 10.1182/bloodadvances.2023010628 -
Cancer Journal (Sudbury, Mass.) 2016Myelofibrosis (MF) is a myeloproliferative neoplasm that presents either as a primary disease or evolves secondarily from polycythemia vera or essential thrombocythemia... (Review)
Review
Myelofibrosis (MF) is a myeloproliferative neoplasm that presents either as a primary disease or evolves secondarily from polycythemia vera or essential thrombocythemia to post-polycythemia vera MF or post-essential thrombocythemia MF, respectively. Myelofibrosis is characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis, constitutional symptoms, cachexia, leukemic progression, and shortened survival. Therapeutic options for patients with MF have been limited to the use of cytoreductive agents, predominantly hydroxyurea; splenectomy and splenic irradiation for treatment of splenomegaly; and management of anemia with transfusions, erythropoiesis-stimulating agents, androgens, and immunomodulatory agents along with steroids. The only curative option is allogeneic stem cell transplantation (ASCT), which is associated with high morbidity and mortality risks. Recently, JAK (Janus kinase) inhibitor therapies have become available and proven to be palliative in primary MF patients with hydroxyurea-refractory splenomegaly and severe constitutional symptoms. The purpose of this article is to review the clinical features of MF; discuss different treatment strategies, including ASCT; and discuss the potential danger and benefit of using JAK inhibitors prior to ASCT.
Topics: Disease Management; Humans; Primary Myelofibrosis; Prognosis; Protein Kinase Inhibitors; Stem Cell Transplantation; Transplantation, Homologous; Treatment Outcome
PubMed: 26841017
DOI: 10.1097/PPO.0000000000000169 -
Cancer Mar 2016Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by... (Review)
Review
Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society.
Topics: Age Factors; Blast Crisis; Clinical Decision-Making; Hemoglobins; Humans; Leukocyte Count; Primary Myelofibrosis; Prognosis; Risk Factors; Thrombosis
PubMed: 26717494
DOI: 10.1002/cncr.29842 -
Current Hematologic Malignancy Reports Jun 2024Summarize best practices for management of patients with early myelofibrosis (MF). (Review)
Review
PURPOSE OF REVIEW
Summarize best practices for management of patients with early myelofibrosis (MF).
RECENT FINDINGS
Myelofibrosis is a progressive myeloproliferative neoplasm (MPN) that generally produces burdensome symptoms and ultimately leads to worse overall survival than that observed in healthy controls or patients with other MPNs. Several Janus kinase inhibitors and various interferon formulations are now available for treatment of MF, with ruxolitinib notable for extending overall survival in addition to improving MF signs and symptoms. The chronic nature of the disease can lead some patients to avoid immediate treatment in favor of a watch-and-wait approach. This review summarizes the patient management approach taken in my practice, providing guidance and a discussion of best practices with an emphasis on the importance and clinical benefits of active treatment in early MF. In particular, a case is made to consider treatment with ruxolitinib for patients with intermediate-1 risk disease and to minimize delay between diagnosis and treatment initiation for patients with intermediate or high-risk disease.
Topics: Humans; Primary Myelofibrosis; Disease Management; Pyrazoles; Pyrimidines; Nitriles; Janus Kinase Inhibitors; Practice Guidelines as Topic
PubMed: 38441783
DOI: 10.1007/s11899-024-00729-8 -
The Oncologist Oct 2015Primary myelofibrosis is a stem cell-derived clonal malignancy characterized by unchecked proliferation of myeloid cells, resulting in bone marrow fibrosis,... (Review)
Review
Primary myelofibrosis is a stem cell-derived clonal malignancy characterized by unchecked proliferation of myeloid cells, resulting in bone marrow fibrosis, osteosclerosis, and pathologic angiogenesis. Bone marrow fibrosis (BMF) plays a central role in the pathophysiology of the disease. This review describes current issues regarding BMF in primary myelofibrosis, including the pathophysiology and impact of abnormal deposition of excess collagen and reticulin fibers in bone marrow spaces, the modified Bauermeister and the European Consensus grading systems of BMF, and the prognostic impact of BMF on the overall outcome of patients with primary myelofibrosis. The impact of novel therapeutic strategies, including JAK-STAT inhibitors and allogeneic stem cell transplant, on BMF is discussed.
Topics: Bone Marrow Cells; Busulfan; Fibrosis; Humans; Janus Kinases; Nitriles; Primary Myelofibrosis; Prognosis; Pyrazoles; Pyrimidines; STAT Transcription Factors; Stem Cell Transplantation
PubMed: 26304912
DOI: 10.1634/theoncologist.2015-0094 -
Biology of Blood and Marrow... Apr 2018The prognosis of myeloproliferative neoplasms, including primary myelofibrosis (PMF), polycythemia vera, and essential thrombocythemia varies considerably, between these... (Review)
Review
The prognosis of myeloproliferative neoplasms, including primary myelofibrosis (PMF), polycythemia vera, and essential thrombocythemia varies considerably, between these disorders as well as within each diagnosis. Molecular studies have identified "driver mutations" in JAK2, MPL1, and CALR and additional somatic DNA mutations, including ASXL1, EZH2, IDH1/2, and SRSF2, that affect prognosis differentially. Patients with mutations in CALR (type1) have a better outlook than patients with mutations in JAK2 or MPL, whereas patients without any of the driver mutations (triple negative) have the shortest life expectancy. Mutations in ASXL1, EZH2, and SRSF2 may be associated with shortened survival, and IDH mutations carry a higher risk of leukemic transformation. The combination and number of mutations are more important than a given single mutation. Mutations also appear to impact the outcome of hematopoietic cell transplantation (HCT), currently the only treatment with curative potential. Based on available data, the best post-HCT outcome is observed with CALR mutations. Triple negativity has a negative impact. The data on JAK2 are controversial. Mutations in ASXL1 or IDH1/2 reduce the probability of progression-free survival after HCT, although the impact of ASXL1 differs between patients with primary and secondary myelofibrosis. Although it is not clear to what extent HCT can overcome the risks associated with a given mutational pattern, at present, early HCT should be considered in triple-negative patients and patients with PMF who harbor mutations in ASXL1. Mutations in EZH2, SRSF2, or IDH, particularly if combined with other mutations, should also lead to consideration of HCT. Further studies are needed to validate the present observations and determine the impact of additional mutations that have been identified.
Topics: Allografts; Decision Making; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Mutation; Neoplasm Proteins; Primary Myelofibrosis; Survival Rate
PubMed: 29128551
DOI: 10.1016/j.bbmt.2017.10.037