Essential Thrombocythemia Research Articles

The characteristics of CALR mutations in myeloproliferative neoplasms: a clinical experience from a tertiary care center in Qatar and a literature review

ABSTRACT Background Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by abnormal production of myeloid cells due to genetic mutations. Since 2013, researchers have identified somatic mutations in the Calreticulin (CALR) gene, primarily insertions or deletions, in two Philadelphia chromosome-negative MPNs; essential thrombocytosis (ET) and primary myelofibrosis (PMF), and occasionally in chronic myelomonocytic leukemia (CMML). This study aims to identify the various types of CALR mutations and their impact on CALR-positive MPN patients’ clinical manifestations and outcomes. Methods A single-center retrospective study was conducted. The data was collected from pre-existing records. The study was carried out on Philadelphia-negative MPN patients who were being followed up on at the NCCCR (National Center for Cancer Care and Research) to assess the clinical manifestation and outcome of disease treatment. All patients included, were followed in our center between January 1, 2008, and November 20, 2021. Results A total of 50 patients with CALR-positive MPN were reviewed with a median follow-up of three years (1–11). This cohort included 31 (62%) patients with ET, 10 (20%) patients with PMF, and 9 (18%) patients with prefibrotic myelofibrosis (pre-MF). The study involved 38 (76%) male and 12 (24%) female patients. There were 16 (32%) patients diagnosed before the age of 40, 24 (48%) patients diagnosed between the ages of 40 and 60; and 10 (20%) patients diagnosed after the age of 60. Molecular analysis showed 24 (48%) patients with CALR type 1, 21 (42%) patients with CALR type 2, and 5 (10%) patients with none Type 1, none Type 2 CALR mutations. Two patients have double mutations; 1(2%) with none Type 1, none Type 2 CALR and JAK2 mutations, and 1(2%) with CALR type 1 and MPL mutations. The thrombotic events were 3 (6%) venous thromboembolisms, 3 (6%) abdominal veins thromboses, 2 (4%) strokes, and 4 (8%) ischemic cardiac events. Only 4 (8%) patients progressed to Myelofibrosis and were carrying CALR 1 mutations, and 1 (2%) patient progressed to AML with CALR 2 mutation. Conclusion The data shows a significant rise in CALR-positive MPN diagnoses in younger people, emphasizing the need for a better assessment tool to improve disease management and reduce complications.

Myeloproliferative Neoplasm Symptom Assessment Total Symptom Score (MPN-SAF TSS) in Chronic Myeloproliferative Neoplasms with Relation to Genetic Burden and Thrombosis

The Myeloproliferative Neoplasm Symptom Assessment Total Symptom Score (MPN-SAF TSS) is a surrogate marker for symptom evaluation in chronic myeloproliferative neoplasms (MPNs). However, insufficient data are available regarding the relationship among the MPN-SAF TSS, JAK2 mutation allele burden, and thrombosis. In this retrospective analysis, we aimed to determine the genetic burdens, clinical features, and relationships with MPN-SAF TSS in MPN patients. One hundred thirty JAK2V617F-positive patients with MPNs were included in our study. We calculated the MPN-SAF TSS for all patients and compared it with their clinical characteristics. Patients with higher JAK2V617F mutation allele burden had higher MPN-SAF TSS values (p=0.008). Patients with thrombosis had higher MPN-SAF TSS than patients without thrombosis (p=0.003). The mean MPN-SAF TSS was higher in patients with primary myelofibrosis compared to those with polycythemia vera and essential thrombocythemia. Thrombosis was associated with increased symptom severity in several domains, including fatigue, abdominal discomfort, inactivity, night sweats, pruritus, weight loss, and early satiety. Additionally, an increase in JAK2 allele burden was observed with higher symptom scores. The MPN-SAF TSS proved to be a reliable tool for assessing symptom burden in Turkish MPN patients. Furthermore, the significant association between thrombosis occurrence and symptom severity suggests that thrombotic events may contribute to symptom development. Notably, increasing JAK2 allele burden was correlated with more severe symptoms, highlighting its potential role in predicting disease burden. This study emphasizes the importance of symptom assessment in MPN patients and supports the incorporation of the MPN-SAF TSS in routine clinical practice to enhance patient care and management.

#2475 Glomerulonephritis associated with anti -TNF-α therapy

Abstract Background and Aims Biologic agents like tumor necrosis factor α inhibitors/ anti-TNF-α/, IL6 and CD80/26 are widely used in many rheumatologic diseases but these may also elicit effects on renal function. These drugs, as well as rheumatic diseases themselves, can cause autoimmune renal disorders. Though effective on the main inflammatory process the incidence of kidney injury associated with their administration is increasing. Various forms of glomerulopathies have been described in connection with biological therapy - proliferative lupus nephritis, oligo immune necrotizing crescentic glomerulonephritis, membranous glomerulonephritis, IgA nephropathy and others. Method We report the clinical and pathologic findings in two patients with Rheumatoid arthritis and Ankylosing spondylitis on biologic therapy with an anti-TNF-α agent. During the treatment they presented with nephritic syndrome requiring kidney histology. Results Case 1: The first patient is a 52-year-old man diagnosed with ankylosing spondylitis, HLA-B27 positive, 15 years before admission. Four years before admission treatment with Golimumab /anti-TNF-α/ has been initiated. During the follow-up period urine tests revealed proteinuria and hematuria, which required more detailed tests. The patient presented with clinical features of nephritic syndrome, marked lower extremity edema, hematuria, nephrotic range proteinuria, impaired hypertension control. Kidney biopsy revealed membranoproliferative glomerulonephritis. It was assumed that kidney injury was most likely associated with Golimumab therapy. Its administration was discontinued, and therapy was started with pulses of Methylprednisolone 500 mg i.v. in three consecutive days, Cyclophosphamide 500 mg i.v., repeated the second and third month, followed by low steroid doses 0,5 mg/kg with gradual tapering. Mycophenolate Mofetil 1500 mg was started from the third month. General condition and laboratory results improved considerably. The occurrence of stiffness and pain in the sacroiliac joints several months after stopping biologic treatment necessitated the inclusion of Sulfasalazine to the therapy. Initiation of therapy with another class of biologic agent, Anti-IL-17 monoclonal antibody, was discussed with the follow-up rheumatologists. Case 2: The second patient is a 66-year-old woman, with a history of hypertension and essential thrombocythemia, who was diagnosed with seropositive rheumatoid arthritis 3 years before admission, treated with Adalimumab /anti-TNF-α/. Follow-up examinations revealed low-grade proteinuria, hematuria and impaired renal function. Kidney biopsy revealed IgA nephropathy. Following the discontinuation of Adalimumab, the patient was treated with pulses of Methylprednisolone 500 mg i.v. in three consecutive days, Cyclophosphamide 500 mg i.v., repeated the second and third month, followed by low steroid doses 0,5 mg/kg with gradual tapering. Kidney function significantly improved at the third month of treatment and proteinuria was gradually reduced. Initiation of Rituximab /antiCD20/ treatment was discussed with rheumatologists. Conclusion Treatment with biological drugs can cause immune-mediated glomerular disorder/IGD/. These events are rare, and the causative effects of a specific drug is hard to establish. When a patient is suspected of having an IGD, kidney biopsy should be performed for the exact diagnosis. The drug should be discontinued, and the treatment for the new-onset renal disorder should be promptly started. A rechallenge test of the same or a similar drug should be avoided, whereas switching to a different therapy is a reasonable option.

The clinical significance of TAT, PIC, TM, and t-PAIC in vascular events of BCR/ABL-negative myeloproliferative neoplasms

Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However, effective assessment methods are lacking. Thrombin-antithrombin complex (TAT), plasmin-α2- plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis. The aim of this study was to investigate the changes of these four new indicators in thrombotic and hemorrhagic events in BCR/ABL1-negative MPN. The study cohort of 74 patients with BCR/ABL negative myeloproliferative disorders included essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF). A panel of 4 biomarkers, including TAT, PIC, TM, and t-PAIC were determined using Sysmex HISCL5000 automated analyzers, whereas fibrin/fibrinogen degradation products (FDP), D-dimer and Antithrombin III (ATIII) were analyzed using Sysmex CS5100 coagulation analyzer. A total of 24 (32.4%) patients experienced thrombotic events and hemorrhagic events occurred in 8 patients (10.8%). Compared to patients without hemorrhagic-thrombotic events, patients with thrombotic events had higher fibrinogen (FIB) level, FDP level and lower ATIII activity, while patients with hemorrhagic events had lower white blood cell count and hemoglobin level, higher FDP level (P < 0.05). Patients with a JAK2V617F mutation were more likely to experience thrombotic events (P < 0.05). In addtion, patients with thrombotic events had higher TAT, PIC, TM, and t-PAIC levels than patients without hemorrhagic-thrombotic events (P < 0.05), whereas patients with hemorrhagic events had a lower median value in TAT and TM (no statistical difference, P > 0.05). Patients with higher TAT, TM and t-PAIC were more likely to experience thrombotic events (P < 0.05), and only TAT was positively correlated with thrombotic events (Spearman r =0.287, P = 0.019). TAT, PIC, TM, and t-PAIC combined with ATIII and FDP have a certain value for predicting thrombosis in patients with BCR/ABL1-negative MPN. These 6 parameters are worth further exploration as predictive factors and prognostic markers for early thrombotic events.

Immunophenotype of myeloid granulocytes in Chinese patients with BCR::ABL1-negative myeloproliferative neoplasms

Typical BCR::ABL1-negative myeloproliferative neoplasms (MPN) are mainly referred to as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofbrosis (PMF). Granulocytes in MPN patients are involved in their inflammation and form an important part of the pathophysiology of MPN patients. It has been shown that the immunophenotype of granulocytes in MPN patients is altered. We used flow cytometry to explore the immunophenotype of MPN patients and correlate it with clinical parameters. The results showed that PMF patients and PV patients had higher CD15+CD11b+ granulocytes than ET patients and normal controls. When grouped by gene mutation, changes in the granulocyte immunophenotype of MPN patients were independent of the JAK2V617F and CALR mutations. There was no significant heterogeneity in immunophenotype between ET patients and Pre-PMF, and between Overt-PMF and Pre-PMF patients. Granulocytes from some MPN patients showed an abnormal CD13/CD16 phenotype with a significant increase in mature granulocytes on molecular and cytomorphological grounds, and this abnormal pattern occurred significantly more frequently in PMF patients than in ET patients. CD15–CD11b– was negatively correlated with WBC and Hb and positively correlated with DIPSS score, whereas high CD10+ granulocytes were significantly and negatively associated with prognostic system IPSS and DIPSS scores in PMF patients. In conclusion, this study demonstrates the landscape of bone marrow granulocyte immunophenotypes in MPN patients. MPN patients, especially those with PMF, have a significant granulocyte developmental overmaturation phenotype. CD10+ granulocytes may be involved in the prognosis of PMF patients.

Initial Low-Dose Hydroxyurea and Anagrelide Combination in Essential Thrombocythemia: Comparable Response with Lower Toxicity.

Background and Objectives: Essential thrombocythemia (ET) is a myeloproliferative neoplasm that overproduces platelets and is associated with life-threatening thrombosis. Medical cytoreduction either with hydroxyurea (HU) or anagrelide (AG) is widely used, but drug intolerance or resistance are major concerns. Low-dose combination of HU and AG as an alternative strategy has been explored in various studies. It showed comparable response with acceptable toxicity in second-line settings for patients who experienced side effects from prior monotherapy. In this study, we evaluated the efficacy and safety of upfront combination for ET patients. Materials and Methods: From January 2018 to June 2022, a total of 241 ET patients with intermediate to high risk were enrolled. We identified 21 patients with initial drug combinations and compared treatment outcomes and adverse events (AEs) between combination and monotherapy groups. Results: The median age was 62 years old (range, 26-87) and median platelet count was 912 × 109/L (range, 520-1720). Overall treatment response did not exhibit significant differences between the groups, although there was a trend towards a lower response rate in patients treated with AG alone at 3 months post-treatment (AG + HU, 85.7% vs. AG alone, 75.4%, p = 0.068). AEs of any grade occurred in 52.3% of the combination group, 44.3% of the HU monotherapy group, and 43.4% of the AG single group, respectively. Of note was that the HU plus AG combination group suffered a lower incidence of grade 3-4 AEs compared to the other two groups, with statistical significance (p = 0.008 for HU monotherapy vs. combination therapy and p < 0.01 for AG monotherapy vs. combination therapy). Conclusions: Our findings demonstrated that the upfront low-dose combination approach showed feasible clinical outcomes with significantly lower severe AEs compared to conventional monotherapy. These results may offer valuable insights to clinicians for future prospective investigations.

Central Retinal Vein Occlusion as the Debut of a Chronic Myeloproliferative Neoplasm

Introduction. Most retinal vascular diseases are associated with systemic risk factors such as hypertension, diabetes mellitus, age and smoking. However, in their absence, further examination is required to identify possible hematological disorders.Purpose. Improve the diagnostic and management scheme for patients with occlusion of the central retinal vein or its branches.Materials and methods. A clinical case of the onset of polycythemia vera with the central retinal vein occlusion is described. As part of the study, a molecular genetic analysis was carried out to identify the driver mutation JAK2V617F in peripheral blood as a screening diagnosis of Ph-negative chronic myeloproliferative neoplasms (CMN), a cytological, cytogenetic study of bone marrow aspirate and a morphological study of bone marrow trephine biopsy.Results. A mutant allele of the JAK2V617F gene with a diagnostically significant allele load of 14.61 % was determined in a patient hospitalized in the ophthalmology department with a diagnosis of central retinal vein occlusion (CRVO) of the right eye. The patient was referred for further examination to the Moscow City Hematology Center of Botkin City Clinical Hospital, where, aſter examination, the diagnosis was established: True polycythemia.Discussion. CMN are a group of tumor diseases of hematopoietic tissue characterized by malignant transformation of bone marrow stem cells with their subsequent clonal proliferation. Cytogenetic and molecular genetic disorders play a significant role in the pathogenesis of chronic CMN. True polycythemia, essential thrombocytemia, primary myelofibrosis belong to the group of classical Ph-negative CMP, Thrombotic, vascular and hemorrhagic complications are the most common causes of death in patients with this pathology.Conclusion. Previously, various ophthalmological manifestations and symptoms have been described in patients with CMN. The observed complications are diverse and oſten secondary to the pathognomonic hematological disorders for these diseases. It is worth considering the clinical value of molecular genetic analysis to detect the JAK2V617F mutation in patients with central retinal vein occlusion for early diagnosis of CMN and timely administration of appropriate therapy.

Clonal evolution process from essential thrombocythemia to acute myeloid leukemia in the original patient from whom the CALR-mutated Marimo cell line was established.

We previously reported the Marimo cell line, which was established from the bone marrow cells of a patient with essential thrombocythemia (ET) at the last stage after transformation to acute myeloid leukemia (AML). This cell line is widely used for the biological analysis of ET because it harbors CALR mutation. However, genetic processes during disease progression in the original patient were not analyzed. We sequentially analyzed the genetic status in the original patient samples during disease progression. The ET clone had already acquired CALR and MPL mutations, and TP53 and NRAS mutations affected the disease progression from ET to AML in this patient. Particularly, the variant allele frequency of the NRAS mutation increased along with the disease progression after transformation, and the NRAS-mutated clone selectively proliferated in vitro, resulting in the establishment of the Marimo cell line. Although CALR and MPL mutations co-existed, MPL was not expressed in Marimo cells or any clinical samples. Furthermore, mitogen-activated protein kinase (MAPK) but not the JAK2-STAT pathway was activated. These results collectively indicate that MAPK activation is mainly associated with the proliferation ability of Marimo cells.

Essential Thrombocythemia Complicated by Addison's Disease: A Case of Overlapping Endocrine and Hematological Disorders

Essential Thrombocythemia Complicated by Addison's Disease: A Case of Overlapping Endocrine and Hematological Disorders

Platelet Factor 4 and Longevity of Patients with Essential Thromobocythemia: An Example of Antagonistic Pathogenic Pleiotropy.

This article presents the concept of Antagonistic Pathogenic Pleiotropy, in which an abnormality that causes a specific pathology can simultaneously reduce other morbidities through unrelated mechanisms, resulting in the pathology causing less morbidity or mortality than expected. The concept is illustrated by the case of essential thrombocythemia (ET). Patients with ET have substantially elevated platelets and are therefore expected to have increased thrombotic events leading to reduced life expectancy. However, patients with ET do not have reduced life expectancy. A possible explanation is that elevated platelets produce higher levels of platelet factor 4 (PF4), which has been found to reduce age-associated decline in immune and cognitive function in mice and has been suggested as a treatment for age-associated illness. The benefit of elevated PF4 is hypothesized to balance the increased morbidity from hematological causes. Searches for other indications where a well-defined pathology is not associated with concomitant reduction in overall mortality may be a route to identifying factors that could protect against, prevent, or treat chronic disease.

Polycythemia vera and essential thrombocythemia of intermediate-age: A real-life, multicenter analysis of first-line treatment approach.

The treatment of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is conducted according to well-defined risk stratification systems. We hypothesized that adherence to the guidelines, namely the decision to refrain from introducing cytoreduction in non-high-risk patients, is particularly difficult in patients diagnosed when they are between 40 and 59 years of age (intermediate-age group). To evaluate the group of intermediate-age PV and ET patients, focusing on a first-line treatment approach adapted at diagnosis. The study group consisted of 308 PV and ET patients recruited from 6 Polish Adult Leukemia Group (PALG) Centers. Patients were analyzed with respect to disease phenotype, risk group, treatment approach, cardiovascular (CV) risk factors, and occurrence of bleeding or thrombosis. Overall, 74% of patients in the study group were started on cytoreduction at diagnosis, including 70% of the low-risk PV patients and 85-89% of the non-high-risk ET patients. Factors influencing the decision to start the treatment included higher hemoglobin (Hb) concentration (in PV) as well as higher platelet (PLT) count, and the presence of CV risk factors (in ET). Introducing cytoreduction at diagnosis had no impact on thrombotic events. Patients harboring CV risk factors experienced a higher incidence of complications both at diagnosis and follow-up, independently of the treatment strategy. We underline the low adherence to recommendations in the treatment of intermediate-age PV and ET patients. Moreover, we emphasize the importance of CV risk factors and stress their impact on disease phenotype in this patient population.

Decreasing circ_0014614 promotes the differentiation of bone marrow flineage cells into megakaryocytes in essential thrombocythemia via activiation of miR-138-5p/caspase3 axis

BackgroundCircular RNAs (circRNA) are pivotal in hematological diseases. Previous study showed that circ_0014614 (circDAP3) was significantly underexpressed in bone marrow–derived exosomes from essential thrombocythemia (ET) patients, affecting the differentiation of bone marrow lineage cells into megakaryocytes. MethodsFluorescence in situ hybridization (FISH) was used to display circ_0014614's primary cytoplasmic location in K562 cells. Cytoscape software was used to predict the circRNA-miRNA-mRNA networks, and their expression at the cellular level was detected by Quantitative reverse transcription-polymerase chain reaction (qRT-PCR). qRT-PCR was utilized to detect the expression levels of circ_0014614，miR-138-5p and caspase3 mRNA. Western blot was used to determine the protein levels of GATA-1, RUNX-1, NF-E2, CD41 and caspase3. The proliferation of K562 cells was assessed using the Cell Counting Kit-8 (CCK-8) Assay. Furthermore, the interplay between miR-138-5p and circ_0014614 or caspase3 was elucidated through a Dual-luciferase reporter assay. ResultsFISH assay indicated circ_0014614's primary cytoplasmic location in K562 cells. In ET bone marrow and K562 cells, circ_0014614 and caspase3 were down-regulated, whereas miR-138-5p saw a significant surge. Overexpressing circ_0014614 curtailed K562 cells' proliferation and differentiation. Further, circ_0014614 targeted miR-138-5p, with heightened miR-138-5p levels counteracting circ_0014614's inhibition. MiR-138-5p further targeted caspase3, and caspase3 silencing neutralized suppressed miR-138-5p's effects on K562 cell differentiation. ConclusionCirc_0014614 was down-regulated in ET bone marrow and bone marrow lineage cells, and upregulating circ_0014614 can inhibit bone marrow lineage cells' proliferation and differentiation into megakaryocytes. Mechanistically, circ_0014614 functioned as ceRNA via sponging miR-138-5p and alleviated the inhibitory effect of miR-138-5p on its target caspase3, which potentially deters tumor activity in ET.

Advances in Molecular Understanding of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis: Towards Precision Medicine.

Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of the molecular pathogenesis of these diseases, with the discovery of key mutations in the JAK2, CALR, and MPL genes being pivotal. This review provides a comprehensive update on the molecular landscape of PV, ET, and PMF, highlighting the diagnostic, prognostic, and therapeutic implications of these genetic findings. We delve into the challenges of diagnosing and treating patients with prognostic mutations, clonal evolution, and the impact of emerging technologies like next-generation sequencing and single-cell genomics on the field. The future of MPN management lies in leveraging these molecular insights to develop personalized treatment strategies, aiming for precision medicine that optimizes outcomes for patients. This article synthesizes current knowledge on molecular diagnostics in MPNs, underscoring the critical role of genetic profiling in enhancing patient care and pointing towards future research directions that promise to further refine our approach to these complex disorders.

Exploring hematological alterations and genetics linked to SNV rs10974944 in myeloproliferative neoplasms among Amazon patients

BCR::ABL1-negative myeloproliferative neoplasms are hematopoietic disorders characterized by panmyelosis. JAK2 V617F is a frequent variant in these diseases and often occurs in the 46/1 haplotype. The G allele of rs10974944 has been shown to be associated with this variant, specifically its acquisition, correlations with familial cases, and laboratory alterations. This study evaluated the association between the 46/1 haplotype and JAK2 V617F in patients with myeloproliferative neoplasms in a population from the Brazilian Amazon. Clinical, laboratory and molecular sequencing analyses were considered. Carriers of the G allele of rs10974944 with polycythemia vera showed an increase in mean corpuscular volume and mean corpuscular hemoglobin, while in those with essential thrombocythemia, there was an elevation in red blood cells, hematocrit, and hemoglobin. Associations were observed between rs10974944 and the JAK2 V617F, in which the G allele (OR 3.4; p < 0.0001) and GG genotype (OR 4.9; p = 0.0016) were associated with JAK2 V617F + and an increase in variant allele frequency (GG: OR 15.8; p = < 0.0001; G: OR 6.0; p = 0.0002). These results suggest an association between rs10974944 (G) and a status for JAK2 V617F, JAK2 V617F + _VAF ≥ 50%, and laboratory alterations in the erythroid lineage.

Renal tubular necrosis associated with anagrelide administration: a case report.

A 62-year-old female patient with essential thrombocythemia experienced rapid renal dysfunction and was subsequently referred to our hospital. Further investigations did not reveal any significant abnormalities except for a slight increase in urinary β2-microglobulin levels. A renal biopsy was performed to investigate the cause of her renal dysfunction, revealing acute tubular necrosis, interstitial edema, and arteriosclerosis. No significant glomerular lesions were observed. Immunofluorescence staining and electron microscopy showed no abnormalities. She had been using anagrelide for 4years, and her dosage was increased from 2.0 to 3.0mg/day 10months before her initial admission. Her renal function began to deteriorate 2months after the anagrelide dosage increase. Although 0.625mg of bisoprolol was initiated for tachycardia 3months after the anagrelide dosage adjustment, we suspected that the acute tubular necrosis was associated with anagrelide administration. After transitioning from anagrelide to hydroxyurea and discontinuing bisoprolol, her renal function improved. This case suggests the importance of considering anagrelide as a potential cause of renal dysfunction in patients using this medication. Therefore, renal biopsy, combined with a comprehensive medical history, is crucial for evaluating the etiology of renal injury in such cases.

Direct and indirect costs for patients with myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability leave and medical claims data to measure direct and indirect healthcare costs associated with MPNs. The analysis included 173 patients with myelofibrosis (MF), 4477 with polycythemia vera (PV), 6061 with essential thrombocythemia (ET), and matched controls (n = 519, n = 13,431, and n = 18,183, respectively). Total healthcare costs were significantly higher for cases versus controls in each cohort (mean cost difference: MF, $67,456; PV, $10,970; ET, $22,279). Cases were more likely than controls to take disability leave and incurred higher disability-related costs. Among subgroups with thrombotic events, direct and indirect costs were higher for cases versus controls. Thrombotic events substantially increased direct costs and disability leave for patients with PV or ET compared with the full PV or ET cohorts. These findings demonstrate increased economic burden for patients with MPNs.

CALR but Not JAK2 Mutations Are Associated with an Overexpression of Retinoid X Receptor Alpha in Essential Thrombocythemia.

Essential thrombocythemia (ET) is a blood cancer caused by mutations in JAK2 and CALR. It is widely recognized that both mutations lead to the constitutive activation of JAK2/STAT signaling, although other JAK/STAT-independent pathogenic mechanisms triggered by these alterations have also been described in ET. In an attempt to study JAK2/STAT-independent mechanisms derived from CALR mutations, our research group created a C. elegans model with patient-like mutations in calreticulin that lacks JAK counterparts. The introduction of patient-like mutations in the calreticulin of C. elegans leads to an increase in the transcriptional expression of nhr-2, independently of JAK2/STAT activation. In the present study, we aim to verify if this mechanism is conserved in patients with ET harboring CALR mutations. To do so, we evaluated the expression of potential orthologs of nhr-2 in human cell lines of interest for the study, as well as in bone marrow (BM) or peripheral blood (PB) mononuclear cells from patients with CALR or JAK2 mutations. The results revealed that this mechanism is conserved in CALR-mutated ET patients, since CALR, but not JAK2 mutations, were associated with an overexpression of RXRA in patients with ET. The use of drugs targeting the activation or blockade of this target in the analyzed cell lines did not result in changes in cell viability. However, RXRA might be relevant in the disease, pointing to the need for future research testing retinoids and other drugs targeting RXRα for the treatment of ET patients.

Real-world status of treatment for lymphoid neoplasms developed during the course of myeloproliferative neoplasms in Japan

ABSTRACT Objectives: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. Methods: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. Results: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. Conclusion: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Sailing in deceptive calm: Navigating the undercurrents of essential thrombocythaemia.

The discovery of driver mutations in myeloproliferative neoplasms has significantly contributed to the management of patients with essential thrombocythaemia (ET). High-quality evidence has started to pave the way for targeted therapy. The review by Ferrer-Marín etal. further advances this discussion, highlighting how molecular profiling, including non-driver gene mutations, is set to revolutionize personalized treatment approaches for ET patients. Commentary on: Ferrer-Marín etal. Essential thrombocythemia: a contemporary approach with new drugs on the horizon. Br J Haematol 2024;204:1605-1616.

Sex-specific impact on disease outcome and the mutational landscape in essential thrombocythemia: A retrospective cohort study.

Sex-specific impact on disease outcome and the mutational landscape in essential thrombocythemia: A retrospective cohort study.