Category Archives: Research

The Role of DNA Repair (XPC, XPD, XPF, and XPG) Gene Polymorphisms in the Development of Myeloproliferative Neoplasms

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by , , , , , and  

Abstract

Background and Objectives: Several polymorphisms have been described in various DNA repair genes. Nucleotide excision DNA repair (NER) detects defects of DNA molecules and corrects them to restore genome integrity. We hypothesized that the XPC, XPD, XPF, and XPG gene polymorphisms influence the appearance of myeloproliferative neoplasms (MPNs). Materials and Methods: We investigated the XPC 1496C>T (rs2228000, XPC Ala499Val), XPC 2920A>C (rs228001, XPC Lys939Gln), XPD 2251A>C (rs13181, XPD Lys751Gln), XPF-673C>T (rs3136038), XPF 11985A>G (rs254942), and XPG 3507G>C (rs17655, XPG Asp1104His) polymorphisms by polymerase chain reaction–restriction fragment length polymorphism analysis in 393 MPN patients [153 with polycythemia vera (PV), 201 with essential thrombocythemia (ET), and 39 with primary myelofibrosis (PMF)] and 323 healthy controls. Results: Overall, we found that variant genotypes of XPD 2251A>C were associated with an increased risk of MPN (OR = 1.54, 95% CI = 1.15–2.08, p = 0.004), while XPF-673C>T and XPF 11985A>G were associated with a decreased risk of developing MPN (OR = 0.56, 95% CI = 0.42–0.76, p < 0.001; and OR = 0.26, 95% CI = 0.19–0.37, p < 0.001, respectively). Conclusions: In light of our findings, XPD 2251A>C polymorphism was associated with the risk of developing MPN and XPF-673C>T and XPF 11985A>G single nucleotide polymorphisms (SNPs) may have a protective role for MPN, while XPC 1496C>T, XPC 2920A>C, and XPG 3507G>C polymorphisms do not represent risk factors in MPN development.

Disease-, Age-, Genomic-Specific Factors Increase Risk of ET, PV, PrePMF Developing Into Overt MF

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Laura Joszt, MA

The risk of essential thrombocytopenia (ET), polycythemia vera (PV), and prefibrotic primary myelofibrosis (PrePMF) developing into overt myelofibrosis (MF) increases with age, the accumulation of mutations, and the activation of proliferative pathways, which identifies new targets for therapeutic intervention.

The findings, based on an analysis of the mutational landscape of more than 1700 genes and the gene expression of various cells from patients with myeloproliferative neoplasms (MPNs), was published in Clinical Cancer Research.1

ET, PV, PMF, and MF are all part of a group of diseases MPNs, in which a mutation in the bone marrow causes too many red blood cells, white blood cells, or platelets.2 In addition to being the most common MPNs, ET, PV, and PMF share the presence of mutations in either Janus kinase 2 (JAK2), calreticulin (CALR), and/or MPL.3 ET and PV are less aggressive forms of MPN, but they still can progress to MF. According to the Leukemia & Lymphoma Society, Pre-PMF will likely progress to PMF, “suggesting that more regular observations for pre-fibrotic PMF patients is warranted.”3

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Childbirth rates in women with myeloproliferative neoplasms

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Published March 9, 2024

Anna Ravn Landtblom, Therese M-L Andersson, Anna L. V. Johansson, Frida E. Lundberg, Jan Samuelsson, Magnus Björkholm & Malin Hultcrantz

Abstract

Myeloproliferative neoplasms (MPN) are associated with inferior pregnancy outcome, however, little is known about fertility and childbearing potential in women with MPN. In this study we aimed to describe reproductive patterns, as well as to quantify risk of miscarriage and stillbirth. Women aged 15–44 years with an MPN diagnosis 1973–2018, were identified in Swedish health care registers, and age-matched 1:4 to population controls. We identified 1141 women with MPN and 4564 controls. Women with MPN had a lower rate of childbirth (hazard ratio [HR] with 95% confidence interval was 0.78 (0.68–0.90)). Subgroup analysis showed that the rate was not significantly reduced in essential thrombocythemia, HR 1.02 (0.86–1.22) while the HR was 0.50 (0.33–0.76) in PV and 0.45 (0.28–0.74) in PMF. The risk of miscarriage was not significantly increased before MPN diagnosis, the HR during follow-up after diagnosis was 1.25 (0.89-1.76). Women with MPN were more likely to have had a previous stillbirth. Women with MPN had fewer children at diagnosis, and fewer children in total. In conclusion, the childbirth rate was lower among women with MPN than controls, but not among women with essential thrombocythemia.

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A Review About the Assessment of the Bleeding and Thrombosis Risk for Patients With Myeloproliferative Neoplasms Scheduled for Surgery

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Mihaela Andreescu
Bogdan Andreescu

Published March 12, 2024

Abstract

Myeloproliferative neoplasms (MPNs) present a unique challenge in surgical management due to their inherent predisposition to both bleeding and thrombosis. MPNs are a heterogenous group of acquired clonal conditions. The three classic MPNs are essential thrombocythemia (ET), myelofibrosis (PMF), and polycythemia vera (PV). All subtypes of MPN are associated with both thrombotic and bleeding complications. There are four risk categories for thrombosis in MPN patients: age, thrombosis history, and JAK-2 mutation. They are further classified as very low, low, intermediate, and high risk. The genetic landscape of MPN is fascinating and complex like all myeloid disorders. Bleeding risk can be assessed through leukocytosis, thrombocytosis, acquired von Willebrand syndrome (AVWS), and a previous history of bleeding in a patient. Risk assessment and perioperative management are important aspects of improving the quality of life and preventing complications in surgeries. Preoperative management includes a risk assessment of venous thromboembolism, use of appropriate pharmacological treatment, platelet count control, and correction and cardiovascular risk factors. This review summarizes the assessment of bleeding and thrombosis risk for patients with MPNs scheduled for surgery. Furthermore, this review discusses various tools that can be used to identify MPN patients at risk of thrombosis prior to surgery.

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Risk of thrombosis, hemorrhage and leukemic transformation in patients with myeloproliferative neoplasms: A nationwide longitudinal cohort study

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Joon Young Hur, Nayeon Choi, Jung Hye Choi, Jiyeong Kim, Young-Woong Won

Abstract

Introduction

There are few large-scale, population-based studies detailing the risks of thrombosis, hemorrhage, leukemic transformation in patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF).

Methods

We performed a nationwide longitudinal cohort study using the Korean National Health Insurance System (NHIS) database. MPN patients (n = 11,991) and their 1:4 age- and sex-matched controls (n = 47,964) were enrolled. The risk of thrombosis, hemorrhage, leukemic transformation was estimated using a Cox proportional hazards regression, and stratified analyses were performed for related factors.

Results

During a median of 7.8 years of follow-up, 30.1 % of MPN patients (3614/11,991) and 19.0 % of the matched controls (9141/47,964) developed arterial thrombosis, 11.6 % of MPN patients (1397/11,991) and 6.4 % of the matched controls (3099/47,964) developed venous thrombosis and 18.7 % of MPN patients (2251/11,991) and 12.1 % of the matched controls (5836/47,964) developed hemorrhage. 4.9 % of MPN patients (597/11,991) and 0.1 % of matched controls (50/47,964) developed leukemia. The overall risk of developing thrombosis, hemorrhage, leukemic transformation was higher in MPN patients (adjusted hazard ratio [aHR] 1.695, 95 % confidence interval [CI]: 1.629–1.765 for arterial thrombosis, aHR 1.963, 95 % CI: 1.838–2.096 for venous thrombosis, and aHR 1.714, 95 % CI: 1.630–1.802 for hemorrhage) than in the controls. Patients with MPNs had a 10-year cumulative incidence of leukemic transformation of 6.2 %.

Conclusion

The patients with MPNs have a higher risk of thrombosis, hemorrhage, and leukemic transformation than matched controls. Strategies are warranted to reduce the risk of thrombosis, hemorrhage, and leukemic transformation in MPN patients.

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Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes

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Luis E. Aguirre, Akriti Jain, Somedeb Ball, Najla Al Ali, Virginia O. Volpe, Sara Tinsley-Vance, David Sallman, Kendra Sweet, Jeffrey Lancet, Eric Padrom, Seongseok Yun, Andrew Kuykendall, Rami Komrokji

Abstract

Background

Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation.

Patients and methods

We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003-2021 and compared them based on presence or absence of the three classical phenotypic driver mutations.

Results

A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; p=.009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (p<0.05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs 63.4%) and shorter duration of response to ruxolitinib.

Conclusion

TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.

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Patients With Myelofibrosis Are at Higher Risk for Poor Cardiovascular Outcomes After Heart Failure Hospitalization

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Grace Taylor

03/05/2024

Patients with myeloproliferative neoplasms (MPN) are at high risk of cardiovascular (CV) disease, including heart failure (HF). Those with myelofibrosis in particular have a higher chance of experiencing HF. In a study presented at the 2023 ASH Annual Meeting & Exposition, Orly Leiva, New York University Grossman School of Medicine, Boston, Massachusetts, and colleagues examined CV outcomes for patients with MPN (essential thrombocythemia [ET], polycythemia vera [PV], or MF) who were hospitalized for HF.

The authors completed a retrospective analysis using data from the National Readmission Database (NRD). They used ICD-10 codes to identify adult patients with a history of MPN who had a primary diagnosis of HF from 2017 and 2018 (N = 4632). Of these patients, 2639 had ET, 1109 had PV, and 884 had MF.

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About 1 in 5 Hematologic Cancer Patients Had Severe COVID-19, Despite Vaccination

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Leah Lawrence

In a study of more than 6000 patients with hematologic cancers, 21% developed severe COVID-19, despite being vaccinated. Researchers reported these results in JAMA Network Open.

The study included 6122 patients from the national Veterans Health Administration who had hematologic cancers. All patients had been vaccinated against COVID-19 but had a confirmed case of COVID-19 between January 1, 2021, and September 30, 2022.

The patients had chronic lymphocytic leukemia (CLL; n=1206) or other non-Hodgkin lymphomas (NHLs; n=1731), plasmacytoid neoplasms (n=1014), myeloproliferative neoplasms (MPNs; n=1144), myelodysplastic syndromes (MDS; n=518), chronic myeloid leukemia (CML; n=180), acute myeloid leukemia (AML; n=172), or Hodgkin lymphoma (n=157).

A total of 1301 paints (21.3%) had severe COVID-19, which was defined as dying within 28 days of SARS-CoV-2 infection, requiring mechanical ventilation, or requiring hospitalization with the use of dexamethasone, evidence of hypoxemia, or the use of supplemental oxygen.

The proportion of patients with severe COVID-19 was similar among those with lymphoid malignancies (21.6%) and those with myeloid malignancies (20.5%). The rate of severe COVID-19 was highest in patient with MDS (28.2%) and lowest in patients with Hodgkin lymphoma (12.1%).

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Non-Driver Gene Mutations Have Adverse Prognostic Impact in Primary Myelofibrosis

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Lauren Dembeck, PhD

A study published in the American Journal of Hematology has confirmed the adverse prognostic impacts of numerous non-driver gene mutations in primary myelofibrosis (PMF).

Researchers analyzed the impact of non-driver somatic mutations in patients with PMF treated at 60 institutions in Spain. Targeted next-generation sequencing (NGS) sequencing evaluating up to 56 non-myeloproliferative neoplasm driver genes was conducted. Of those, the team focused on 20 genes consistently analyzed across NGS panels. Only pathogenic or likely-pathogenic genetic variants with a variant allele frequency (VAF) higher than 1% were considered mutations.

A total of 312 patients with PMF according to World Health Organization criteria at the time of diagnosis and with availability of NGS data were included in the analysis. The median age of the cohort was 68 years. At a median follow-up duration of 4 years, 9% of patients had progressed to acute myeloid leukemia, and 47% had died.

Overall, 72% of patients had non-driver mutations, with 47% having 2 or more mutations (range, 0-7). The most frequent mutations detected were in ASXL1 (34%), TET2 (22%), SRSF2 (17%), U2AF1 Q157 (9%), CBL (8%), EZH2 (7%), TP53 (6%), DNMT3A (6%), and SETBP1 (5%).

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Years After Genetic Finding, Drugs Targeting CALR-Mutant Myeloproliferative Neoplasms Enter Trials

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Feb 29, 2024 | Catherine Shaffer

NEW YORK – More than a decade after mutations in the CALR gene were first linked to the development of myeloproliferative neoplasms, CALR-targeted drug candidates are advancing to Phase I clinical trials.

If these drugs reach the market, they could provide a treatment option for a group of patients with myelofibrosis and essential thrombocythemia who typically must wait until their condition turns serious to attempt a risky stem cell transplant.

About 300,000 patients in the US have myeloproliferative neoplasms. Kapila Vigas, CEO of the MPN Research Foundation, said patients can have very different presentations of the disease, and it can take “years or decades” to get a diagnosis. Although myeloproliferative neoplasms are classified as chronic cancers that patients can live with for many years with blood count monitoring, Vigas said some patients can abruptly progress, and their condition can become serious.

“That uncertainty is really concerning to patients,” Vigas said. “We think from a psychosocial perspective, it’s worse than an acute cancer because while cancer may be more serious, it’s predictable, and there’s a plan and a protocol, whereas when you’re diagnosed with [a myeloproliferative neoplasm] watch and wait is almost a first-line approach. It just adds to the anxiety.”

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