JAK2 V617F polycythemia vera and essential thrombocythemia: dynamic clinical features associated with long-term outcomes.
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SUBMITTER: Sureau L
PROVIDER: S-EPMC8993923 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
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JAK2 V617F polycythemia vera and essential thrombocythemia: dynamic clinical features associated with long-term outcomes.
Sureau Léa L Buors Caroline C Ianotto Jean-Christophe JC Boyer Françoise F Tanguy-Schmidt Aline A Roy Lydia L Cayssials Emilie E Cailly Laura L Chomel Jean-Claude JC Chauveau Aurélie A Orvain Corentin C Mansier Olivier O Ranta Dana D Robles Margot M Gyan Emmanuel E Hérault Olivier O Nimubona Stanislas S Marchand Tony T Lippert Eric E Riou Jérémie J Ugo Valérie V Luque Paz Damien D
Blood cancer journal 20220408 4
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| S-EPMC8448748 | biostudies-literature
Project description:Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells; these include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPNs are inflammatory cancers, wherein the malignant clone generates cytokines that sustain the inflammatory drive in a self-perpetuating vicious cycle. The course of MPNs follows a biological continuum, that is, from early cancer stages (ET/PV) to advanced myelofibrosis as well as impending leukemic transformation. MPN-related symptoms, e.g., fatigue, general weakness, and itching, are caused by inflammatory cytokines. Thrombosis and bleeding are also exacerbated by inflammatory cytokines in patients with MPN. Until recently, the primary objective of ET and PV therapy was to increase survival rates by preventing thrombosis. However, several medications have recently demonstrated the ability to modify the course of the disease; symptom relief is expected for most patients. In addition, there is increasing interest in the active treatment of patients at low risk with PV and ET. This review focuses on the ET/PV treatment strategies as well as novel treatment options for clinical development.
| S-EPMC10133851 | biostudies-literature
Project description:Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2V617F mutation. The study had a standard 3+3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2V617F-positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4h after single and multiple doses, and mean half-life on day 1 was approximately 6h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥120mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120.
| S-EPMC8207330 | biostudies-literature
Project description:Polycythemia vera (PV) is characterized by JAK2 and essential thrombocythemia (ET) by JAK2, calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) mutations; we describe the occurrence and prognostic relevance of DNA sequence variants/mutations other than JAK2/CALR/MPL. A myeloid neoplasm-relevant 27-gene panel was used for next-generation sequencing of bone marrow or whole blood DNA and conventional tools were used for analysis. "Adverse variants/mutations" were identified by age-adjusted multivariable analysis of impact on overall, leukemia-free, or myelofibrosis-free survival. Fifty-three percent of 133 Mayo Clinic patients with PV and 53% of 183 with ET harbored 1 or more sequence variants/mutations other than JAK2/CALR/MPL; the most frequent were TET2 and ASXL1. "Adverse variants/mutations" in PV included ASXL1, SRSF2, and IDH2 and in ET SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2; combined prevalence was 15% and 15%, respectively. Adverse variants/mutations were associated with inferior survival in both PV (median, 7.7 vs 16.9 years) and ET (median, 9 vs 22 years) and the effect was independent of conventional prognostic models with respective hazard ratio (95% confidence interval) of 2.8 (1.5-5.1) and 2.6 (1.4-4.8); these observations were validated in 215 Italian patients with PV and 174 with ET. In both Mayo Clinic and Italian cohorts, leukemic or fibrotic progression was also predicted by adverse variants/mutations. Number of mutations did not provide additional prognostic information. We conclude that targeted deep sequencing in PV and ET allows for genetic risk stratification that is independent of clinically derived prognostic models.
| S-EPMC5744051 | biostudies-literature
Project description:BackgroundIn order to facilitate sound economic evaluations of novel treatments, health-economic models of polycythemia vera (PV) must combine effects on surrogate endpoints in trials with disease progression (DP) and mortality in long-term cohort data.ObjectiveWe validate an economic model for PV that uses Janus Kinase 2 (JAK2) burden as a surrogate endpoint to predict DP (thrombosis, myelofibrosis, and acute leukemia) and overall survival (OS) based on progression-specific mortality.MethodsLong-term observational studies that include information about baseline JAK2 burden were identified via PubMed searches and used to validate the model. Kaplan-Meier (KM) OS curves were extracted using a digitizing software. External validity of the model was analyzed by visually comparing OS curves of the model with the KM curves of the included studies, as well as calculating differences in mean OS estimated as area under the curve (AUC).ResultsThe model's predictions of cumulative DP were somewhat lower than the published studies. Over 20 years' time, our base case model predicted a mean OS for a PV patient (15.0-16.5 years), which was in line with the published studies (15.8-17.5 years). Modeled mean OS was almost two years longer (1.6-1.9 years) for patients with JAK2 <50% than patients with JAK2 ≥50%. Only three long-term observational studies that satisfied the predefined criteria were found and could be used in the validation, but these studies did not capture JAK2 evolution over time. Improved model predictions of DP and mortality based on the longitudinal evolution of JAK2 could be derived from real-world data sources. Such data are currently scarce and future observational studies should be designed to capture the long-term impact of JAK2 on DP and mortality in PV.ConclusionsOur model, based on JAK2 burden as a marker for DP, generated OS estimations that are in line with results of published data.
| S-EPMC7343343 | biostudies-literature
Project description:Polycythemia vera (PV) and essential thrombocythemia (ET) are both driven by JAK-STAT pathway activation and consequently much of the recent research efforts to improve the management and outcomes of patients with these neoplasms have centered around inhibition of this pathway. In addition to newer JAK inhibitors and improved interferons, promising novel agents exploiting a growing understanding of PV and ET pathogenesis and disease evolution mechanisms are being developed. These agents may modify the disease course in addition to cytoreduction. Histone deacetylase, MDM2 and telomerase inhibitors in patients with PV/ET have demonstrated clinically efficacy and serve as chief examples. Hepcidin mimetics, limiting iron availability to red blood cell precursors, offer an exciting alternative to therapeutic phlebotomy and have the potential to revolutionize management for patients with PV. Many of these newer agents are found to improve hematologic parameters and symptom burden, but their role in thrombotic risk reduction and disease progression control is currently unknown. The results of larger, randomized studies to confirm the early efficacy signals observed in phase 1/2 trials are eagerly awaited.
| S-EPMC8161993 | biostudies-literature
Project description:Polycythemia vera (PV) and essential thrombocythemia (ET) are both classic, relatively indolent, chronic Philadelphia-chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) characterized by elevated blood counts, thrombotic as well as hemorrhagic tendencies, a variety of symptoms, cumulative risks of progression to myelofibrosis and transformation to acute myeloid leukemia over time, and long survival. Molecularly, PV is more homogenous, being driven by JAK2 mutations in virtually all cases, while ET can be JAK2-, CALR-, or MPL-mutated, as well as 'triple negative'. Recent targeted next-generation sequencing efforts have identified other, nondriver gene mutations, some with prognostic relevance. Prevention of thrombotic and hemorrhagic complications continues to be the major focus of management, although symptoms are increasingly being recognized as a relatively unmet need, particularly in ET. Thrombotic risk stratification in PV is still based on age and history of thrombosis, while in ET, the additional contribution of JAK2 V617F to thrombotic risk is now well established. The associations of leukocytosis with clotting risk (in both conditions) and mortality (in PV) have drawn increased attention with the availability of ruxolitinib as a second-line treatment in PV. Similarly, there is a renewed interest in interferons with the emergence of ropeginterferon alfa-2b as a potential new frontline treatment option in PV. Drug development is more difficult in ET, the most indolent of the classic Ph- MPNs, but ruxolitinib is being studied. Triggering apoptosis via the p53 pathway through pharmacologic inhibition of human double minute 2 (and synergism with interferon) is a new, promising therapeutic strategy.
| S-EPMC6719465 | biostudies-literature
Project description:BackgroundPegylated-interferon alpha (PegINFα) treatment of patients with polycythemia vera (PV) and essential thrombocythemia (ET) has resulted in long-term clinical response, decreased JAK2V617F allelic burden and restoration of polyclonal hematopoiesis. The mechanisms of the beneficial effects of PegINFα are not clear, but available evidence suggests direct suppression of JAK2-mutated clone, induction of dormant stem cells to proliferation, and augmentation of an immune effect against PV and ET clones.MethodsWe analyzed the phenotype and frequency of peripheral blood lymphocytes (PBL) from PegINFα treated patients and compared them to patients treated with hydroxyurea (HU). Samples collected at various time points before and during treatment were analyzed using multicolor flow cytometry.ResultsWe found that PegINFα increased the frequency of peripheral blood CD4+ Foxp3+ regulatory T cells (Treg). Highly suppressive Treg, characterized by co-expression of CD39 and HLA-DR, were also increased in PBL from PegINFα treated patients. We observed an augmentation of cycling CD8+ T cells, NK cells, and of poorly activated CD38+CD8+ T cells. Our results also suggest that PegINFα increased the frequency of PD-1+ CD4+ helper cells and PD-1+ CD4+ Foxp3+ Treg cells. None of these changes were present in HU treated patients. We analyzed the correlation between changes in different T cell populations in the peripheral blood with the changes in JAK2V617F allelic burden in clonal granulocytes. Augmentation of Ki-67+ Treg, HLA-DR+ CD39+ Treg, Helios+ Treg and HLA-DR+ CD38+ CD8+ T cells correlated with an increase in JAK2V617F allelic burden. We also found a positive correlation between PD-1+ Treg and JAK2V617F allelic burden; however, the number of available patients was small (n = 7).ConclusionsWe report marked changes in frequencies of PBL subsets after PegINFα treatment, suggesting an immunomodulatory effect by PegINFα. Generation of a more suppressive immune response, as measured by an increase in highly suppressive Treg and poorly activated CD8+ T cells, correlated with a poor molecular response. In this study, we have not identified changes in the PBL that would indicate the presence of an effective anti-tumor response.Trial registration NCT01259856, December 7. 2010 and NCT01259817, December 6. 2010, Grant #1P01CA108671-O1A2, July 17. 2006, Sponsor: MPDRC/NIH, NCI-2012-00269, January 12. 2011 and NCI-2012-00268, January 12. 2011.
| S-EPMC5037882 | biostudies-literature
Project description:BackgroundDespite recent advances in the investigation of myeloproliferative neoplasms (MPN), the impact of genetic heterogeneity on its molecular pathogenesis has not been fully elucidated. Thus, in this study, we aim to characterize the genetic complexity in Korean patients with polycythemia vera (PV) and essential thrombocythemia (ET).MethodsWe conducted association studies using 84 single-nucleotide polymorphisms (SNPs) in 229 patients (96 with PV and 133 with ET) and 170 controls. Further, whole-genome sequencing was performed in six patients (two with JAK2 V617F and four with wild-type JAK2), and putative somatic mutations were validated in a further 69 ET patients. Clinical and laboratory characteristics were also analyzed.ResultsSeveral germline SNPs and the 46 haplotype were significantly associated with PV and ET. Three somatic mutations in MPDZ, IQCH, and CALR genes were selected and validated. The frequency of the CALR mutation was 58.0% (40/69) in ET patients, who did not carry JAK2/MPL mutations. Moreover, compared with JAK2 V617F-positive patients, those with CALR mutations showed lower hemoglobin and hematocrit levels (P = 0.004 and P = 0.002, respectively), higher platelet counts (P =0.008), and a lower frequency of cytoreductive therapy (P = 0.014).ConclusionThis study was the first comprehensive investigation of the genetic characteristics of Korean patients with PV and ET. We found that somatic mutations and the 46 haplotype contribute to PV and ET pathogenesis in Korean patients.
| S-EPMC6807207 | biostudies-literature
Project description: Not available
| S-EPMC4532371 | biostudies-literature