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Future Oncology (London, England) 2015The JAK1 and JAK2 inhibitor ruxolitinib has approved indications in myelofibrosis, a BCR-AB1-negative myeloproliferative neoplasm associated with progressive bone marrow... (Review)
Review
The JAK1 and JAK2 inhibitor ruxolitinib has approved indications in myelofibrosis, a BCR-AB1-negative myeloproliferative neoplasm associated with progressive bone marrow fibrosis and shortened survival. In Phase III clinical studies, ruxolitinib provided rapid and durable improvement of myelofibrosis-related splenomegaly and symptoms irrespective of mutation status, and was associated with a survival advantage compared with placebo or best available therapy. Because of dose-dependent cytopenias, blood count monitoring and dose titration are important to optimize therapy. Specific precautions apply to the treatment of patients with or at risk of serious infections. Discontinuation of ruxolitinib generally leads to symptom return within 1 week. Ruxolitinib also is approved for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Janus Kinases; Nitriles; Primary Myelofibrosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome
PubMed: 25757677
DOI: 10.2217/fon.14.272 -
Biology of Blood and Marrow... Sep 2017Myeloproliferative neoplasm (MPN) is a category in the World Health Organization classification of myeloid tumors. BCR-ABL1-negative MPN is a subcategory that includes... (Review)
Review
Myeloproliferative neoplasm (MPN) is a category in the World Health Organization classification of myeloid tumors. BCR-ABL1-negative MPN is a subcategory that includes primary myelofibrosis (MF), post-essential thrombocythemia MF, and post-polycythemia vera MF. These disorders are characterized by stem cell-derived clonal myeloproliferation. Clinically, these diseases present with anemia and splenomegaly and significant constitutional symptoms such as severe fatigue, symptoms associated with an enlarged spleen and liver, pruritus, fevers, night sweats, and bone pain. Multiple treatment options may provide symptom relief and improved survival; however, allogeneic stem cell transplantation (HCT) remains the only potentially curative option. The decision for a transplant is based on patient prognosis, age, comorbidities, and functional status. This review describes the recent data on various peritransplantation factors and their effect on outcomes of patients with MF and new therapeutic areas, such as the use and timing of Janus kinase inhibitors with HCT and gives overall conclusions from the available data in the published literature.
Topics: Cell Proliferation; Disease Management; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Histocompatibility Testing; Humans; Janus Kinase Inhibitors; Polycythemia Vera; Primary Myelofibrosis; Splenomegaly; Survival Analysis; Thrombocythemia, Essential; Tissue Donors; Transplantation, Homologous; Treatment Outcome
PubMed: 28499938
DOI: 10.1016/j.bbmt.2017.05.007 -
Blood Cancer Journal Sep 2019Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by ineffective clonal hematopoiesis, splenomegaly, bone marrow fibrosis, and the propensity for... (Review)
Review
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by ineffective clonal hematopoiesis, splenomegaly, bone marrow fibrosis, and the propensity for transformation to acute myeloid leukemia. The discovery of mutations in JAK2, CALR, and MPL have uncovered activated JAK-STAT signaling as a primary driver of MF, supporting a rationale for JAK inhibition. However, JAK inhibition alone is insufficient for long-term remission and offers modest, if any, disease-modifying effects. Given this, there is great interest in identifying mechanisms that cooperate with JAK-STAT signaling to predict disease progression and rationally guide the development of novel therapies. This review outlines the latest discoveries in the biology of MF, discusses current clinical management of patients with MF, and summarizes the ongoing clinical trials that hope to change the landscape of MF treatment.
Topics: Female; Gene Amplification; History, 21st Century; Humans; Janus Kinase 2; Male; Primary Myelofibrosis; Protein Kinase Inhibitors
PubMed: 31511492
DOI: 10.1038/s41408-019-0236-2 -
Hematology/oncology Clinics of North... Apr 2021Myelofibrosis (MF) belongs to a group of clonal stem cell disorders known as the BCR-ABL-negative myeloproliferative neoplasms. Allogeneic hematopoietic stem cell... (Review)
Review
Myelofibrosis (MF) belongs to a group of clonal stem cell disorders known as the BCR-ABL-negative myeloproliferative neoplasms. Allogeneic hematopoietic stem cell transplantation (HCT) is currently the only curative treatment option for MF. Because HCT can be associated with significant morbidity and mortality, patients need to be carefully selected based on disease-risk, fitness, and transplant factors. Furthermore, in the era of JAK inhibitors, the timing of transplantation has become a challenging question. Here the authors review recent developments in HCT for MF, focusing on risk stratification and optimal timing.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Myeloproliferative Disorders; Primary Myelofibrosis
PubMed: 33641876
DOI: 10.1016/j.hoc.2020.12.004 -
Experimental Hematology Oct 2017Bone marrow fibrosis is a critical component of primary myelofibrosis in which normal bone marrow tissue and blood-forming cells are gradually replaced with scar tissue.... (Review)
Review
Bone marrow fibrosis is a critical component of primary myelofibrosis in which normal bone marrow tissue and blood-forming cells are gradually replaced with scar tissue. The specific cellular and molecular mechanisms that cause bone marrow fibrosis are not understood. A recent study using state-of-the-art techniques, including in vivo lineage tracing, provides evidence that Gli1 cells are the cells responsible for fibrotic disease in the bone marrow. Strikingly, genetic depletion of Gli1 cells rescues bone marrow failure and abolishes myelofibrosis. This work introduces a new central cellular target for bone marrow fibrosis. The knowledge that emerges from this research will be important for the treatment of several malignant and nonmalignant disorders.
Topics: Animals; Bone Marrow; Bone Marrow Cells; Cell Proliferation; Disease Models, Animal; Gene Expression; Humans; Mice; Mice, Transgenic; Molecular Targeted Therapy; Platelet Factor 4; Primary Myelofibrosis; Pyridines; Pyrimidines; Zinc Finger Protein GLI1
PubMed: 28690072
DOI: 10.1016/j.exphem.2017.06.349 -
Blood Cancer Journal Jul 2023
Topics: Humans; Primary Myelofibrosis; Thrombocythemia, Essential; Motivation; Thrombosis; Bone Marrow
PubMed: 37507408
DOI: 10.1038/s41408-023-00887-7 -
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 -
Current Hematologic Malignancy Reports Oct 2022Philadelphia-negative myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic (pre-), and overt-primary... (Review)
Review
PURPOSE OF REVIEW
Philadelphia-negative myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic (pre-), and overt-primary myelofibrosis (primary MF, PMF). PV and ET could evolve into secondary MF (SMF), whose early diagnosis relies on monitoring signs of possible progression. All MPNs have a risk of blast phase (BP), that is associated with a very dismal outcome. Overall survival (OS) is different among MPNs, and disease-specific prognostic scores should be applied for a correct clinical management. In this review, an overview of current prognostic scores in MPNs will be provided.
RECENT FINDINGS
The biological complexity of MPNs and its role on the trajectory of disease outcome have led to the design of integrated prognostic models that are nowadays of common use in PMF patients. As for PV and ET, splicing gene mutations could have a detrimental role, but with the limit of the not routinary recommended application of extensive molecular analysis in these diseases. SMF is recognized as a distinct entity compared to PMF, and OS estimates should be calculated by the MYSEC-PM (Myelofibrosis SECondary-prognostic model). Both in PMF and SMF, decisions as selection of patients potentially candidates to allogenic stem cell transplant or that could benefit from an early shift from standard treatment are based not only on conventional prognostic scores, but also on multivariable algorithms. The expanding landscape of risk prediction for OS, evolution to BP, and SMF progression from PV/ET informs personalized approach to the management of patients affected by MPNs.
Topics: Humans; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Thrombocythemia, Essential
PubMed: 36048275
DOI: 10.1007/s11899-022-00672-6 -
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 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