DOI•
New Perspectives of Interferon-alpha2 and Inflammation in Treating Philadelphia-negative Chronic Myeloproliferative Neoplasms.
18 Nov 2021-Vol. 5, Iss: 12
About: The article was published on 2021-11-18 and is currently open access. It has received 9 citations till now.
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TL;DR: This rIFNα- mediated dampening of genotoxic damage to hematopoietic cells may ultimately diminish the risk of additional mutations and accordingly clonal evolution and disease progression towards myelofibrotic and leukemic transformation.
Abstract: Chronic inflammation is considered a major driving force for clonal expansion and evolution in the Philadelphia-negative myeloproliferative neoplasms, which include essential thrombocythemia, polycythemia vera and primary myelofibrosis (MPNs). One of the key mutation drivers is the JAK2V617F mutation, which has been shown to induce the generation of reactive oxygen species (ROS). Using whole blood gene expression profiling, deregulation of several oxidative stress and anti-oxidative defense genes has been identified in MPNs, including significant downregulation of TP53, the NFE2L2 or NRF2 genes. These genes have a major role for maintaining genomic stability, regulation of the oxidative stress response and in modulating migration or retention of hematopoietic stem cells. Therefore, their deregulation might give rise to increasing genomic instability, increased chronic inflammation and disease progression with egress of hematopoietic stem cells from the bone marrow to seed in the spleen, liver and elsewhere. Interferon-alpha2 (rIFNα) is increasingly being recognized as the drug of choice for the treatment of patients with MPNs. Herein, we report the first gene expression profiling study on the impact of rIFNα upon oxidative stress and antioxidative defense genes in patients with MPNs (n = 33), showing that rIFNα downregulates several upregulated oxidative stress genes and upregulates downregulated antioxidative defense genes. Treatment with rIFNα induced upregulation of 19 genes in ET and 29 genes in PV including CXCR4 and TP53. In conclusion, this rIFNα- mediated dampening of genotoxic damage to hematopoietic cells may ultimately diminish the risk of additional mutations and accordingly clonal evolution and disease progression towards myelofibrotic and leukemic transformation.
3 citations
TL;DR: In this article , the authors present results of randomized clinical trials (RCT) that evaluated ROPEG in the treatment of polycythemia vera (PV) patients.
Abstract: ABSTRACT Introduction Interferons (IFNs) have been used for decades to treat polycythemia vera (PV). Single-arm clinical trials assessing IFN in PV patients demonstrated high hematological and molecular response rates, indicating potential disease-modifying activity of IFN. However, discontinuation rates of IFNs have been rather high due to frequent treatment-related side-effects. Areas covered Ropeginterferon alfa-2b (ROPEG) is a monopegylated IFN consisting of a single isoform, which differentiates it from previous IFNs with respect to tolerability and dosing frequency. ROPEG has improved pharmacokinetic and pharmacodynamic properties, which allow extended dosing every 2 weeks and monthly administration during maintenance phase. This review covers ROPEG’s pharmacokinetic and pharmacodynamic properties, presents results of randomized clinical trials (RCT) that evaluated ROPEG in the treatment of PV patients, and discusses contemporary findings regarding the potential disease-modifying activity of ROPEG. Expert opinion RCT have demonstrated high rates of hematological and molecular responses in PV patients treated with ROPEG, irrespective of thrombotic risk. Drug discontinuation rates were generally low. However, even though RCT captured the most important surrogate endpoints of thrombotic risk and disease progression in PV, they were not statistically powered to fully determine whether therapeutic intervention with ROPEG indeed has a direct positive effect on these important clinical outcomes.
2 citations
TL;DR: In this article , the authors present current, detailed knowledge on the pathogenic mechanisms specifically associated with polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and the MPL and CALR mutations, found in ET and PMF.
Abstract: Knowledge on the myeloproliferative neoplasms (MPNs) – polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) – has accumulated since the discovery of the JAK/STAT-activating mutations associated with MPNs: JAK2V617F, observed in PV, ET and PMF; and the MPL and CALR mutations, found in ET and PMF. The intriguing lack of disease specificity of these mutations, and of the chronic inflammation associated with MPNs, triggered a quest for finding what precisely determines that MPN patients develop a PV, ET or PMF phenoptype. The mechanisms of action of MPN-driving mutations, and concomitant mutations (ASXL1, DNMT3A, TET2, others), have been extensively studied, as well as the role played by these mutations in inflammation, and several pathogenic models have been proposed. In parallel, different types of drugs have been tested in MPNs (JAK inhibitors, interferons, hydroxyurea, anagrelide, azacytidine, combinations of those), some acting on both JAK2 and inflammation. Yet MPNs remain incurable diseases. This review aims to present current, detailed knowledge on the pathogenic mechanisms specifically associated with PV, ET or PMF that may pave the way for the development of novel, curative therapies.
TL;DR: In this article , the authors describe a healthy CALR mutated individual during a 12 year follow-up from initial identification of CALR clonal hematopoiesis of indeterminate potential (CHIP) to the diagnosis of pre-MF.
Abstract: Initial diagnosis of overt myeloproliferative neoplasms (MPNs) represents the juncture during clonal evolution when symptoms or complications prompt an afflicted individual to seek medical attention. In 30-40% of the MPN subgroups essential thrombocythemia (ET) and myelofibrosis (MF), somatic mutations in the calreticulin gene (CALR) are drivers of the disease resulting in constitutive activation of the thrombopoietin receptor (MPL). In the current study, we describe a healthy CALR mutated individual during a 12 year follow-up from initial identification of CALR clonal hematopoiesis of indeterminate potential (CHIP) to the diagnosis of pre-MF. The pre-diagnostic exponential development dynamics of the malignant clone demonstrated close correlation with the platelet counts, neutrophil-to-lymphocyte (NLR) ratio, and inversely correlated to hemoglobin and erythrocyte counts. Backward extrapolation of the growth rate indicated the potential for discovery of the malignant clone many years prior to presentation of overt disease, opening a window of opportunity for early treatment intervention. We did not find any additional mutations associated with MPNs and the current case report provides novel information regarding the development of a driver mutation and the association with blood cell counts prior to clinical manifestation of symptoms suggesting that pre-diagnostic dynamics may supplement future diagnostic criteria for early diagnosis and intervention in MPN patients.
TL;DR: The use of IFN in the treatment of JAK2V617F mutation-positive ET and PV patients yields a prominent clinical effect by prolonging PFS and avoiding phlebotomy for JAK 2V617f mutation- positive PV patients.
Abstract: Objective To investigate the clinical significance and safety of interferon in the treatment of chronic myeloproliferative tumors (MPN). Methods In this prospective study, a total of 120 patients with advanced chronic MPN admitted to our hospital between April 2016 and August 2020 were assessed for eligibility and recruited, including 62 patients with JAK2V617F mutation-positive ET (ET group) and 58 patients with JAK2V617F mutation-positive PV (PV group). 62 patients with JAK2V617F mutation-positive ET were assigned (1 : 1) to receive interferon-α (IFN-α) or hydroxyurea (HU). A similar subgrouping method for treatment of IFN-α and HU was introduced to patients with JAK2V617F mutation-positive PV. Outcome measures included efficacy and adverse reactions. Results For patients with JAK2V617F mutation-positive ET and PV, there were no significant differences in the overall response rate between the groups treated with IFN-α or HU (P > 0.05); however, the patients treated with IFN-α had a significantly higher 5-year progression-free survival (PFS) than those treated with HU (P < 0.05). IFN-α was associated with a significantly lower incidence of disease progression, thrombotic events, splenomegaly, myelofibrosis, nausea, and vomiting and a higher incidence of hematological adverse reactions and flu-like symptoms versus HU (P < 0.05). After six months of treatment, the PV group had 12 cases of hematological response both in the IFN-α subgroup and the HU subgroup and fewer PV patients treated with IFN-α required phlebotomy versus those treated with HU (P < 0.05), in which 4 patients in the IFN-α subgroup had no hematological response and 6 patients in the HU subgroup had no hematological response. There was no significant difference in the number of cases with phlebotomy between the two subgroups of PV patients without hematological response (P > 0.05). Conclusion The use of IFN in the treatment of JAK2V617F mutation-positive ET and PV patients yields a prominent clinical effect by prolonging PFS and avoiding phlebotomy for JAK2V617F mutation-positive PV patients.
References
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TL;DR: The reduced cancer-related mortality among statin users as compared with those who had never used statins was observed for each of 13 cancer types, suggesting a need for trials of statins in patients with cancer.
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