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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 -
F1000Research 2023Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell diseases characterised by myeloid cell growth from one or more lineages. Angiogenesis, in contrast...
Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell diseases characterised by myeloid cell growth from one or more lineages. Angiogenesis, in contrast to other subtypes, plays a substantial role in the pathophysiology of primary myelofibrosis (PMF). Research expressing the correlation of microvessel density (MVD), blasts, fibrosis and mast cell count in MPN cases are rarely conducted. We aimed to study the significance of MVD in correlation with CD34 blasts, mast cells and fibrosis in bone marrow biopsies of MPN patients. The current research was a cross sectional study conducted on 66 cases diagnosed as MPN during a six-year period. This comprised of 32 chronic myeloid leukemia (CML), 31 PMF and three essential thrombocythemia (ET) cases. Routine staining along with reticulin stain to look for fibrosis and immunohistochemistry (IHC) using CD34 and mast cell tryptase (MCT) were performed. We found increased MVD in PMF, when compared to CML and ET (p = 0.042). Further, mean MVD was observed to be increased with high blast counts (p = 0.036). On follow up, raised mean MVD was seen in those cases with relapse/deceased as compared to disease-free patients, which was highly significant (p = 0.000). Increased MVD score was mostly associated with PMF subtype among all the MPNs. Further, higher MVD was observed to be associated with increased blast count and poor prognosis. With angiogenesis playing a critical role in disease outcome, we now have drugs to regulate angiogenesis that are supported by contemporary research. However, further studies with larger cohorts to establish the theranostic role of MVD in MPNs is recommended.
Topics: Humans; Bone Marrow; Microvascular Density; Cross-Sectional Studies; Myeloproliferative Disorders; Cell Count; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Antigens, CD34; Fibrosis
PubMed: 38434629
DOI: 10.12688/f1000research.130522.2 -
Turkish Journal of Haematology :... Mar 2024In this study, we investigated the effects of calreticulin () and V617F mutational status on clinical course and disease outcomes in Turkish patients with essential...
OBJECTIVE
In this study, we investigated the effects of calreticulin () and V617F mutational status on clinical course and disease outcomes in Turkish patients with essential thrombocythemia (ET).
MATERIALS AND METHODS
Seventeen centers from Türkiye participated in the study and - and V617F-mutated ET patients were evaluated retrospectively.
RESULTS
A total of 302 patients were included, of whom 203 (67.2%) and 99 (32.8%) were V617F- and -positive, respectively. -mutated patients were significantly younger (51 years vs. 57.5 years, p=0.03), with higher median platelet counts (987x10/L vs. 709x10/L, p<0.001) and lower median hemoglobin levels (13.1 g/dL vs. 14.1 g/dL, p<0.001) compared to V617F-mutated patients. Thromboembolic events (TEEs) occurred in 54 patients (17.9%), 77.8% of which were arterial. Compared to mutation, V617F was associated with a higher risk of thrombosis (8.1% vs. 22.7%, p=0.002). Rates of transformation to myelofibrosis (MF) and leukemia were 4% and 0.7%, respectively, and these rates were comparable between V617F- and -mutated cases. The estimated overall survival (OS) and MF-free survival of the entire cohort were 265.1 months and 235.7 months, respectively. OS and MF-free survival durations were similar between V617F- and -mutated patients. Thrombosis-free survival (TFS) was superior in -mutated patients compared to V617F-positive patients (5-year TFS: 90% vs. 71%, respectively; p=0.001). Age at diagnosis was an independent factor affecting the incidence of TEEs.
CONCLUSION
In our ET cohort, mutations resulted in higher platelet counts and lower hemoglobin levels than V617F and were associated with younger age at diagnosis. V617F was strongly associated with thrombosis and worse TFS. Hydroxyurea was the most preferred cytoreductive agent for patients with high thrombosis risk.
Topics: Humans; Calreticulin; Disease Progression; Hemoglobins; Mutation; Primary Myelofibrosis; Retrospective Studies; Thrombocythemia, Essential; Thrombosis; Turkey
PubMed: 38433449
DOI: 10.4274/tjh.galenos.2024.2023.0430 -
Indian Journal of Pathology &... Feb 2024Acute panmyelosis with myelofibrosis (APMF) corresponds to <1% cases of acute myeloid leukemia, which could be an underestimation due to missed diagnosis. Due to its...
Acute panmyelosis with myelofibrosis (APMF) corresponds to <1% cases of acute myeloid leukemia, which could be an underestimation due to missed diagnosis. Due to its rapidly fatal course, it warrants a timely and correct diagnosis. We present a case of a 44-year male who came with a short history of fever, generalised weakness, revealed pancytopenia with occasional circulating blast in the peripheral blood smear. Bone marrow aspirate was dry tap,biopsy revealed panmyelosis with myelofibrosis with increased (22%) blasts. Flowcytometric immunophenotyping, cytogenetics and molecular tests were undertaken. Together with clinical details, immunophenotypic profile, cytogenetics and molecular studies, the diagnosis of Acute panmyelosis with myelofibrosis was made and managed accordingly. 32 The WHO 2017 describes APMF as an acute panmyeloid proliferation with increased blasts (≥20% in the bone marrow or peripheral blood) and accompanying marrow fibrosis. APMF is rare with poor prognosis thus, must be differentiated especially from Acute megakaryoblastic leukemia to arrive at the correct diagnosis which will help reduce/prevent the early mortality by providing timely chemotherapy followed by upfront hemopoietic stem cell transplantation.
PubMed: 38427772
DOI: 10.4103/ijpm.ijpm_391_23 -
Haematologica Jul 2024BCR::ABL1 negative myeloproliferative neoplasms (MPN) form a distinct group of hematologic malignancies characterized by sustained proliferation of cells from multiple... (Review)
Review
BCR::ABL1 negative myeloproliferative neoplasms (MPN) 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 MPN. Additionally, for a significant subset of patients, MPN evolve 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 (BM) and peripheral blood (PB), MPN may be considered to be typical inflammation-related malignancies. However, the exact role and consequences of increased cytokine concentrations within BM and PB plasma has still not been completely established. Up-regulated cytokines can stimulate cellular proliferation, or contribute to the development of an inflammation-related BM niche resulting in genotoxicity and thereby supporting mutagenesis. The neutrophil chemoattractant CXCL8 is of specific interest as its concentration is increased within PB and BM 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 BM fibrosis and megakaryocyte dysmorphia in murine models. In 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.
Topics: Humans; Receptors, Interleukin-8B; Primary Myelofibrosis; Animals; Receptors, Interleukin-8A; Interleukin-8; Signal Transduction
PubMed: 38426279
DOI: 10.3324/haematol.2023.284921 -
Pharmacology Research & Perspectives Apr 2024Parsaclisib, a potent and selective phosphatidylinositol 3 kinase δ inhibitor, has been investigated for the treatment of B-cell malignancies and studied in patients...
Evaluation of the cardiac safety of parsaclisib, a selective PI3Kδ inhibitor, in patients with previously treated B-cell malignancies: Results from the CITADEL-101 study.
Parsaclisib, a potent and selective phosphatidylinositol 3 kinase δ inhibitor, has been investigated for the treatment of B-cell malignancies and studied in patients with autoimmune diseases and myelofibrosis. The CITADEL-101 study (NCT02018861) assessed safety, tolerability, and preliminary efficacy of parsaclisib in patients with relapsed or refractory non-Hodgkin lymphoma. This study evaluated the cardiac safety of parsaclisib as monotherapy based on data from 72 patients enrolled in the CITADEL-101 study. Time-matched pharmacokinetic and ECG measurements were collected at specified times for 69 patients receiving monotherapy in doses of 5, 10, 15, 20, 30, and 45 mg once daily. Based on the categorical outlier analysis, no dose-dependent effect was observed on the incidence of outliers in QT interval corrected for heart rate (HR) by Fridericia's method (QTcF), HR, or cardiac conduction. Based on central tendency analysis, the least square means (LSMs) (90% confidence interval [CI]) of ΔQTcF from the central tendency analysis ranged from -6.83 (-18.8 to 5.19) to 4.75 ms (0.410-9.09) across dose groups (below 20 ms, the threshold of large QT effects) and was not considered dose dependent. Moreover, the LSMs of ΔHR, ΔPR interval, and ΔQRS interval were minor. From the concentration-ΔQTcF analyses, the predicted ΔQTcF (90% CI) for all dose levels was between 0.365 (-1.75 to 2.48) and 7.87 ms (0.921-14.8), with the highest upper limit of CIs well below 20 ms, and therefore, a large QT/QTc effect was ruled out up to the highest dose level (45 mg) investigated. Overall, parsaclisib at the dose ranges studied did not reveal concentration-dependent effects on change in QTcF and did not have a significant effect on HR or cardiac conduction.
Topics: Humans; Pyrazoles; Pyrrolidines; Heart; Neoplasms; Pyrimidines
PubMed: 38407508
DOI: 10.1002/prp2.1165 -
EJHaem Feb 2024The simultaneous detection of :: and V617F was rarely reported and their clonal relationship and dynamic clonal shift were not characterized. Here, we described a...
The simultaneous detection of :: and V617F was rarely reported and their clonal relationship and dynamic clonal shift were not characterized. Here, we described a unique case with the initial presentation as V617F+ primary myelofibrosis, followed by the emergence of + chronic myeloid leukemia. The patient then developed B-lymphoblastic leukemia. Treatment for B-lymphoblastic leukemia prompted a regression to the state of primary myelofibrosis. In light of these observations, we proposed a clonal evolution model for this case.
PubMed: 38406521
DOI: 10.1002/jha2.806 -
EJHaem Feb 2024Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between...
Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor-naive patients from SIMPLIFY-1 (NCT01969838), a double-blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, = .350; ruxolitinib, = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, = .126; ruxolitinib, = .407)/symptom (momelotinib, = .617; ruxolitinib, = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1-grade BMF improvement (momelotinib, = .395; ruxolitinib, = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors.
PubMed: 38406514
DOI: 10.1002/jha2.854 -
Indian Journal of Pathology &... Apr 2024Anemia coexisting with Gaucher disease (GD) is often associated with non-hemolytic processes. Few cases of GD with autoimmune hemolytic anemia have been reported....
Anemia coexisting with Gaucher disease (GD) is often associated with non-hemolytic processes. Few cases of GD with autoimmune hemolytic anemia have been reported. However, literature on GD with concomitant nonimmune hemolytic anemia is scarce. A 1-year 6-month-old male child presented in 2018 with complaints of palpable mass in left upper abdomen, fever, cough, and vomiting. On examination, he had pallor, hepatosplenomegaly of 2 cm and 8 cm below costal margin, respectively. A clinical diagnosis of hemolytic anemia was suspected. Complete blood count revealed Hb---6.7 g/dL, TLC---8.9 × 10 3 /μL, platelet count---180 × 10 3 /μL. Peripheral smear showed predominantly microcytic hypochromic anemia with moderate degree of anisocytosis, many nucleated red blood cells, few schistocytes, polychromatophils and corrected reticulocyte count 7.89%. S. Bilirubin was 1.1 mg/dL. Hb high-performance liquid chromatography (HPLC) of the child and his parents was within normal limit. Hematological work up revealed negative results for direct Coombs' test, osmotic fragility test, and sickling test. Test for Glucose-6-phosphate dehydrogenase deficiency was positive (39 units/trillion RBC, normal 146--376). He was transfused intermittently and given steroids to manage his anemia. He was on regular follow up during which his blood counts revealed persistent anemia and thrombocytopenia. In view of this, bone marrow was performed to exclude myelofibrosis. Aspirate smears were cellular and showed normoblastic erythroid hyperplasia. Numerous large histiocytes with basophilic fibrillary cytoplasm exhibiting "crumpled tissue paper" appearance were seen. Similar findings were seen on bone marrow trephine biopsy. Genetic testing revealed pathogenic variations in the GBA gene. Beta glucosidase enzyme levels were low while chitotriosidase was raised (1109.19 nmol/hr/mL). A final diagnosis of G6PD with GD was made. The present study shows rare association of GD with Glucose-6-phosphate dehydrogenase deficiency.
Topics: Humans; Gaucher Disease; Male; Glucosephosphate Dehydrogenase Deficiency; Infant; Bone Marrow
PubMed: 38391334
DOI: 10.4103/ijpm.ijpm_271_22 -
Clinical Cancer Research : An Official... May 2024Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of...
PURPOSE
Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of Bcr-Abl-ve MPN, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF), and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear.
EXPERIMENTAL DESIGN
To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1,711 genes for mutations along with whole transcriptome RNA sequencing of 137 patients with MPN.
RESULTS
In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N = 106) and ET/PV/PrePMF (N = 31), respectively. Overt MF had more mutations compared with ET/PV/prePMF (5 vs. 4 per subject, P = 0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1) and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2, and NF1 were exclusive to MF. Advancing age, higher DIPSS, and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2, and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells.
CONCLUSIONS
Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression and potential targets for therapeutic intervention.
Topics: Humans; Primary Myelofibrosis; Mutation; Middle Aged; Aged; Male; Female; High-Throughput Nucleotide Sequencing; Adult; Aged, 80 and over; Genomics; Age Factors; Gene Expression Profiling; Transcriptome; Polycythemia Vera
PubMed: 38386293
DOI: 10.1158/1078-0432.CCR-23-0372