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Expert Review of Hematology Mar 2022Given the progressive nature of myelofibrosis, the incidence of thrombocytopenia increases over time. Furthermore, approved drugs ruxolitinib and fedratinib, induce... (Review)
Review
INTRODUCTION
Given the progressive nature of myelofibrosis, the incidence of thrombocytopenia increases over time. Furthermore, approved drugs ruxolitinib and fedratinib, induce thrombocytopenia. Hence, treatment of myelofibrosis patients with low platelet counts is an unmet need.
AREAS COVERED
This review summarizes the current and emerging treatment options available for patients with myelofibrosis and thrombocytopenia. In the first section of this review, we summarized the use of JAK inhibitors in patients with thrombocytopenia, and in the second part, we focused on use of therapies other than JAK Inhibitors such as steroids, immunomodulatory agents, androgens and other novel agents.
EXPERT OPINION
Up to 25% of patients with myelofibrosis have platelet counts below 100,000 at presentation. Patients with thrombocytopenia are more likely to be anemic and PRBC transfusion-dependent, as well as have high-risk disease characteristics and a poor overall survival rate. Among all JAK inhibitors studied in phase 3 clinical trials, pacritinib seems not to induce significant thrombocytopenia while maintaining a good spleen response. Severe thrombocytopenia is a major impediment to myelofibrosis therapy, and more research, particularly on novel therapeutic agents aimed at cytopenic patient populations, is needed.
Topics: Anemia; Humans; Janus Kinase Inhibitors; Primary Myelofibrosis; Protein Kinase Inhibitors; Thrombocytopenia
PubMed: 35316110
DOI: 10.1080/17474086.2022.2057296 -
Journal of Clinical Oncology : Official... Feb 2018Purpose To develop a prognostic system for transplantation-age patients with primary myelofibrosis (PMF) that integrates clinical, cytogenetic, and mutation data.... (Comparative Study)
Comparative Study
Purpose To develop a prognostic system for transplantation-age patients with primary myelofibrosis (PMF) that integrates clinical, cytogenetic, and mutation data. Patients and Methods The study included 805 patients with PMF age ≤ 70 years recruited from multiple Italian centers and the Mayo Clinic (Rochester, MN), forming two independent learning and validation cohorts. A Cox multivariable model was used to select from among a list of 22 variables those that were predictive of overall survival (OS). Integrated clinical and genetic prognostic models with (MIPSS70-plus) or without (MIPSS70) cytogenetic information were developed. Results Multivariable analysis identified the following as significant risk factors for OS: hemoglobin < 100 g/L, leukocytes > 25 × 10/L, platelets < 100 × 10/L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms, absence of CALR type-1 mutation, presence of high-molecular risk mutation (ie, ASXL1, EZH2, SRSF2, IDH1/ 2), and presence of two or more high-molecular risk mutations. By assigning hazard ratio (HR)-weighted points to these variables, three risk categories were delineated for the MIPSS70 model; 5-year OS was 95% in low-risk, 70% in intermediate-risk, and 29% in high-risk categories, corresponding to median OS of 27.7 years (95% CI, 22 to 34 years), 7.1 years (95% CI, 6.2 to 8.1 years), and 2.3 years (95% CI, 1.9 to 2.7 years), respectively. In the MIPSS70-plus model, which included cytogenetic information, four risk categories were delineated, with 5-year OS of 91% in low-risk, 66% in intermediate-risk (HR, 3.2; 95% CI, 1.9 to 5.2), 42% in high-risk (HR, 6.4; 95% CI, 4.1 to 10.0), and 7% very high-risk categories (HR, 17.0; 95% CI, 9.8 to 29.2). Both models remained effective after inclusion of older patients in the analysis. Conclusion MIPSS70 and MIPSS70-plus provide complementary systems of risk stratification for transplantation-age patients with PMF and integrate prognostically relevant clinical, cytogenetic, and mutation data.
Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Cytogenetic Analysis; DNA Mutational Analysis; Decision Support Techniques; Female; Genetic Predisposition to Disease; Humans; Italy; Male; Middle Aged; Minnesota; Mutation; Phenotype; Predictive Value of Tests; Primary Myelofibrosis; Prognosis; Reproducibility of Results; Risk Assessment; Risk Factors; Stem Cell Transplantation; Time Factors; Young Adult
PubMed: 29226763
DOI: 10.1200/JCO.2017.76.4886 -
Journal of Clinical Oncology : Official... Jun 2018
Topics: DNA Mutational Analysis; Humans; Karyotype; Mutation; Primary Myelofibrosis; Prognosis
PubMed: 29708808
DOI: 10.1200/JCO.2018.78.9867 -
Hematology. American Society of... Dec 2023Myelofibrosis is a devastating myeloid malignancy characterized by dysregulation of the JAK-STAT pathway, resulting in splenomegaly, constitutional symptoms, anemia,... (Review)
Review
Myelofibrosis is a devastating myeloid malignancy characterized by dysregulation of the JAK-STAT pathway, resulting in splenomegaly, constitutional symptoms, anemia, thrombocytopenia, leukocytosis, and an increased likelihood of progression to acute leukemia. The only curative option is allogeneic stem cell transplantation. The numbers of transplants have been increasing every year, and although there have been improvements in survival, there remain many unanswered questions. In this review, we will evaluate patient selection and appropriate timing for transplantation. We will cover the current prognostic scoring systems, which can aid in the decision of when to move forward with transplant. We will also review the different donor options, as well as the conditioning regimens. The peritransplant management of splenomegaly will be reviewed. We will discuss management of posttransplant complications such as loss of donor chimerism or disease relapse. Finally, we will review what is known about the outlook of patients who have undergone allogeneic stem cell transplant with regards to quality of life and long-term survival.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Janus Kinases; Primary Myelofibrosis; Quality of Life; Signal Transduction; Splenomegaly; STAT Transcription Factors; Transplantation Conditioning; Treatment Outcome
PubMed: 38066916
DOI: 10.1182/hematology.2023000453 -
Clinical Lymphoma, Myeloma & Leukemia May 2022Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly,... (Review)
Review
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms and acute myeloid leukemia progression. Currently, allogeneic haematopoietic stem cell transplantation (AHSCT) therapy is the only curative option for MF patients. However, AHSCT is strictly limited due to the high rates of morbidity and mortality. Janus kinase 2 (JAK2) inhibitor Ruxolitinib is the first-line treatment for intermediate-II or high-risk MF patients with splenomegaly and constitutional symptoms, but most MF patients develop resistance or intolerance to Ruxolitinib. Therefore, MF treatment is a challenge for the medical community. This review summarizes 3 investigated directions for MF therapy: monotherapies of JAK inhibitors, monotherapies of non-JAK targeted agents, combination therapies of Ruxolitinib and other agents. We emphasize combination of Ruxolitinib and other agents is a promising strategy.
Topics: Anemia; Hematopoiesis; Humans; Primary Myelofibrosis; Splenomegaly
PubMed: 34903489
DOI: 10.1016/j.clml.2021.11.007 -
Journal of Hematology & Oncology Sep 2017Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.
METHODS
This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.
RESULTS
A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23-0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36-0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.
CONCLUSIONS
These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.
TRIAL REGISTRATION
ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .
Topics: Anemia; Disease Progression; Double-Blind Method; Female; Humans; Male; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Survival Analysis; Treatment Outcome
PubMed: 28962635
DOI: 10.1186/s13045-017-0527-7 -
Leukemia & Lymphoma May 2022Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis... (Review)
Review
Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis and hepatosplenomegaly, increased pro-inflammatory cytokine production, and systemic symptoms. Patients with MF also have a propensity toward leukemic transformation. Allogeneic hematopoietic stem cell transplantation (aHCT) is the only curative therapy for patients with MF; however, transplant-related morbidity and mortality precludes this option for the majority of patients. In the last decade, two targeted therapies have been approved for the treatment of MF, both JAK2 inhibitors, ruxolitinib and fedratinib. Despite the clinical efficacy of these two compounds in terms of splenomegaly and symptom burden reduction, there remain many areas of unmet need in the treatment of myelofibrosis. In this review, we discuss the limitations of currently approved treatment options and novel therapeutic targets with drug candidates in late-stage (phase II or III) clinical development for the treatment of MF. We delve into the mechanism of action and scientific rational of each candidate agent as well as the available clinical data, and ongoing trials that could lead to the approval of some of these novel therapies.
Topics: Humans; Janus Kinase Inhibitors; Myeloproliferative Disorders; Primary Myelofibrosis; Splenomegaly; Treatment Outcome
PubMed: 34852713
DOI: 10.1080/10428194.2021.2010068 -
Current Treatment Options in Oncology Feb 2023Currently approved therapies for myelofibrosis (MF) consist of JAK inhibitors, which produce meaningful improvements in spleen size and symptom burden but do not... (Review)
Review
Currently approved therapies for myelofibrosis (MF) consist of JAK inhibitors, which produce meaningful improvements in spleen size and symptom burden but do not significantly impact leukemic progression. In addition, many patients develop resistance or intolerance to existing therapies and are left without meaningful therapeutic options. There has been recent rapid development of agents in MF that may be able to fill these unmet needs. Importantly, most treatments currently in clinical development have targets outside the JAK-STAT pathway, including BET, BCL-2/BCL-xL, PI3k, HDM2, PIM-1, SINE, telomerase, LSD1, and CD123. These therapies are being tested in combination with JAK inhibitors in the front-line setting and in patients with a suboptimal response, as well as a single agent after JAK inhibitor failure. This next generation of agents is likely to produce a paradigm shift in MF treatment with a focus on combination treatment targeting multiple areas of MF pathophysiology.
Topics: Humans; Primary Myelofibrosis; Janus Kinases; Janus Kinase Inhibitors; STAT Transcription Factors; Signal Transduction; Protein Kinase Inhibitors
PubMed: 36640223
DOI: 10.1007/s11864-023-01052-9 -
Orbit (Amsterdam, Netherlands) Jun 2022A 69-year-old man with myelofibrosis presented with a two-day history of left periorbital swelling, blurred vision, and non-radiating dull orbital pain. On examination,... (Review)
Review
A 69-year-old man with myelofibrosis presented with a two-day history of left periorbital swelling, blurred vision, and non-radiating dull orbital pain. On examination, there was restricted left-sided extraocular motility with conjunctival injection, chemosis, and periorbital edema. Magnetic resonance imaging demonstrated left-sided pre- and post-septal fat stranding concerning for orbital cellulitis. Two weeks before symptom onset, the patient began fedratinib therapy for myelofibrosis but discontinued this medication upon hospital admission. After restarting fedratinib, he presented with similar right-sided ophthalmic signs. A review of his medication history revealed a temporal relationship between symptom onset and fedratinib use. After medication discontinuation, his symptoms improved rapidly.
Topics: Aged; Humans; Inflammation; Male; Orbital Cellulitis; Primary Myelofibrosis; Pyrrolidines; Sulfonamides
PubMed: 33243070
DOI: 10.1080/01676830.2020.1852263 -
International Journal of Molecular... Dec 2023Myelofibrosis (MF), Myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes have a broad range of clinical presentations and molecular abnormalities, making... (Review)
Review
Myelofibrosis (MF), Myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes have a broad range of clinical presentations and molecular abnormalities, making their diagnosis and classification complex. This paper reviews molecular aberration, epigenetic modifications, chromosomal anomalies, and their interactions with cellular and other immune mechanisms in the manifestations of these disease spectra, clinical features, classification, and treatment modalities. The advent of new-generation sequencing has broadened the understanding of the genetic factors involved. However, while great strides have been made in the pharmacological treatment of these diseases, treatment of advanced disease remains hematopoietic stem cell transplant.
Topics: Humans; Myeloproliferative Disorders; Primary Myelofibrosis; Chromosome Aberrations; Neoplasms; Mutation
PubMed: 38139212
DOI: 10.3390/ijms242417383