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New Insights into Myeloproliferative Neoplasms
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New Insights into Myeloproliferative Neoplasms

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 114667

Special Issue Editor

Prof. Dr. Hans Hasselbalch

E-Mail Website
Guest Editor
Department of Hematology, Zealand University Hospital, University of Copenhagen, Roskilde, Denmark
Interests: chronic myeloproliferative neoplasms (MPNs); gene expression profiling; epigenetics; SNPs; immune cell and molecular studies in MPNs; epidemiological studies; interferon-alpha2 (IFN-alpha2); statins; ruxolitinib in the treatment of MPNs

Special Issue Information

Dear Colleagues,

In recent years, new insights into the Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have emerged, including the important role of chronic inflammation as the driving force for clonal evolution and disease progression and the impact of chronic inflammation upon symptom burden as well. The role of interferon-alfa2 (IFN) in the initial treatment of MPNs has been increasingly recognized, being fueled by the EU marketing authorization for RopegInterferon Alfa2b (BesremiR) as first line monotherapy in adults for the treatment of PV without symptomatic splenomegaly. The “wait and watch strategy” in low-risk patients is currently being challenged, since treatment with IFN may induce minimal residual disease (MRD) with low-burden JAK2V617F and normal bone marrow after about five years of IFN-treatment. Next generation sequencing is being used increasingly at the time of diagnosis for early prognostication and guidance for treatment. Most recent studies have unraveled MPNs to be far more prevalent than previously recognized, underscoring the unmet need of much earlier diagnosis of MPNs by molecular screening of patients at risk of having undiagnosed MPNs. This might also imply an earlier diagnosis of second cancers which MPN-patients are prone to develop, likely as a consequence of chronic inflammation, immunoderegulation and associated defective tumor immune surveillance.

This Special Issue will highlight several of the above issues, including mathematical modelling studies, substantiating the proof of concept for chronic inflammation as a trigger and driver of MPN development, and underscoring the importance of initiating IFN-treatment as early as possible. A new bright future for patients with MPNs is foreseen, in whom early intervention with stem cell targeted therapy (IFN) or IFN in combination with agents targeting the chronic inflammatory state (e.g., ruxolitinib and statins) may open the avenue for many more patients to follow the path towards MRD, and even cure being obtained by vaccination strategies.

Prof. Dr. Hans Hasselbalch
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Philadelphia-negative myeloproliferative neoplasms (MPNs)
  • chronic inflammation
  • comorbidity burden
  • quality of life
  • early diagnosis and treatment
  • immune therapy
  • interferon-alpha2
  • vaccination
  • minimal residual disease
  • cure

Published Papers (27 papers)

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Research

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18 pages, 719 KiB  
Article
Health-Related Quality of Life in Patients with Philadelphia-Negative Myeloproliferative Neoplasms: A Nationwide Population-Based Survey in Denmark
by Nana Brochmann, Esben Meulengracht Flachs, Anne Illemann Christensen, Marie Bak, Christen Lykkegaard Andersen, Knud Juel and Ann-Dorthe Zwisler
Cancers 2020, 12(12), 3565; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123565 - 28 Nov 2020
Cited by 10 | Viewed by 2301
Abstract
Previous studies have clarified that many patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) have burdensome symptom profiles and accordingly impaired functioning and quality of life (QoL). In Denmark, all MPN patients are affiliated with public hospitals and because of a healthcare system financed by [...] Read more.
Previous studies have clarified that many patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) have burdensome symptom profiles and accordingly impaired functioning and quality of life (QoL). In Denmark, all MPN patients are affiliated with public hospitals and because of a healthcare system financed by taxpayers these patients do not have any financial costs related to the hematological disease. Diagnoses are recorded for all patients in hospitals, and diagnosis codes are communicated to the National Patient Register (NPR). Owing to this, it was possible to contribute to the elucidation of Philadelphia-negative MPN patients’ health-related quality of life (HRQoL), by conducting a nationwide, population-based, cross-sectional HRQoL survey of these patients with cost-free access to the best available, suitable medical treatment. The survey contained validated questionnaires covering functioning, symptom burden, symptom profile, QoL, and additional questions on lifestyle. Information on comorbid diagnoses was obtained from the NPR. The participants’ HRQoL was compared to the general population. Moreover, differences in HRQoL across essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN participants were investigated, adjusted for age, sex, comorbidity, and lifestyle. To the best of our knowledge this is the first survey of HRQoL in patients with unclassifiable MPN. A total of 2228 Philadelphia-negative MPN patients participated. The participants reported their HRQoL to be inferior to the general population, but the difference was minor. The differences in HRQoL across groups of participants with different MPN subtypes were subtle. Fatigue and sexual problems were prevalent and burdensome. Overall, participants reported a slightly healthier lifestyle compared to the general population. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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11 pages, 808 KiB  
Article
Treosulfan-Based Conditioning Regimen for Second Allograft in Patients with Myelofibrosis
by Isik Kaygusuz Atagunduz, Evgeny Klyuchnikov, Christine Wolschke, Dietlinde Janson, Silke Heidenreich, Maximilian Christopeit, Francis Ayuk and Nicolaus Kröger
Cancers 2020, 12(11), 3098; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113098 - 23 Oct 2020
Cited by 9 | Viewed by 2189
Abstract
Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less [...] Read more.
Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36–42 g/m2) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related (n = 2), unrelated (n = 23), or mismatched unrelated (n = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II–IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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14 pages, 715 KiB  
Article
Risk of Inflammatory Bowel Disease in Patients with Chronic Myeloproliferative Neoplasms: A Danish Nationwide Cohort Study
by Marie Bak, Tine Jess, Esben Meulengracht Flachs, Ann-Dorthe Zwisler, Knud Juel and Henrik Frederiksen
Cancers 2020, 12(9), 2700; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092700 - 21 Sep 2020
Cited by 11 | Viewed by 3775
Abstract
An association between hematological cancers and inflammatory bowel disease (IBD) has previously been suggested, but the risk of IBD in patients with myeloproliferative neoplasms (MPNs) is unknown. We conducted a nationwide population-based cohort study using Danish registries, to estimate the risk of IBD [...] Read more.
An association between hematological cancers and inflammatory bowel disease (IBD) has previously been suggested, but the risk of IBD in patients with myeloproliferative neoplasms (MPNs) is unknown. We conducted a nationwide population-based cohort study using Danish registries, to estimate the risk of IBD in individuals diagnosed with essential thrombocythemia, polycythemia vera, myelofibrosis or unclassifiable MPN during 1994–2013. MPN patients were matched 1:10 with sex- and age-matched comparisons. Everyone was followed until a diagnosis of IBD, death/emigration, or 31 December 2013. The risk of IBD overall and according to MPN subtype was calculated using Cox regression and presented as hazard ratios (HRs) with 95% confidence intervals (CI). Of 8207 MPN patients followed for 45,232 person-years, 80 were diagnosed with IBD (61 ulcerative colitis, 19 Crohn’s disease). The rate of IBD per 1000 person-years was 1.8 (95% CI:1.4–2.2) in patients vs. 0.8 (95% CI:0.7–0.8) in comparisons, and the absolute 10-year risk of IBD was 0.8% (95% CI:0.6–1.0) in patients vs. 0.4% (95% CI:0.4–0.5) in comparisons. The HR of IBD was 2.4 (95% CI:2.1–2.9) with similar HRs for ulcerative colitis and Crohn’s disease. MPN subtype risks varied from 2.1 (95% CI:1.6–2.7) to 2.8 (95% CI:2.1–3.7). Our unselected cohort study showed a more than 2-fold increased risk of IBD in MPN patients. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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13 pages, 1785 KiB  
Article
Modification of the Histone Landscape with JAK Inhibition in Myeloproliferative Neoplasms
by Graeme Greenfield, Suzanne McPherson, James Smith, Adam Mead, Claire Harrison, Ken Mills and Mary Frances McMullin
Cancers 2020, 12(9), 2669; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092669 - 18 Sep 2020
Cited by 6 | Viewed by 2737
Abstract
Dysregulation of epigenetic processes is increasingly understood to play a role in the pathogenesis of myeloproliferative neoplasms (MPNs). Ruxolitinib, a JAK/STAT inhibitor, has proved a useful addition to the therapeutic arsenal for these disorders, but has limited disease modifying activity. We determined the [...] Read more.
Dysregulation of epigenetic processes is increasingly understood to play a role in the pathogenesis of myeloproliferative neoplasms (MPNs). Ruxolitinib, a JAK/STAT inhibitor, has proved a useful addition to the therapeutic arsenal for these disorders, but has limited disease modifying activity. We determined the effect of JAK inhibition on the histone landscape of MPN cells in cell line models of MPNs and validated using samples from the MAJIC randomised clinical trial of ruxolitinib in polycythaemia vera and essential thrombocythaemia. We demonstrated an epigenetic modifying effect of ruxolitinib using a histone modification assay. The majority of 21 histone H3 modifications were upregulated, with H3K27me3 and H3K36me2 significant in the combined cell line results. Chromatin immunoprecipitation and sequencing (CHIP-seq) for three marks of interest, H3K4me1, H3K4me3 and H3K27ac, was consistent with the histone modification assay showing a significant increase in H3K4me3 and H3K27ac peaks at promoter regions, both marks of active transcription. In contrast, RNA sequencing demonstrates a coordinated reduction in gene expression in a number of cell pathways including PI3K-AKT signalling, transcriptional misregulation in cancer and JAK-STAT signalling in spite of these histone changes. This highlights the complex mechanisms of transcriptional control within the cells which was reflected in analysis of the histone landscape in patient samples following ruxolitinib treatment. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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24 pages, 3594 KiB  
Article
Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms
by Sophie Allain-Maillet, Adrien Bosseboeuf, Nicolas Mennesson, Mégane Bostoën, Laura Dufeu, Eun Ho Choi, Cédric Cleyrat, Olivier Mansier, Eric Lippert, Yannick Le Bris, Jean-Marc Gombert, François Girodon, Magali Pettazzoni, Edith Bigot-Corbel and Sylvie Hermouet
Cancers 2020, 12(9), 2446; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092446 - 28 Aug 2020
Cited by 11 | Viewed by 2746
Abstract
Inflammatory cytokines play a major role in myeloproliferative neoplasms (MPNs) as regulators of the MPN clone and as mediators of clinical symptoms and complications. Firstly, we investigated the effect of JAK2V617F on 42 molecules linked to inflammation. For JAK2V617F-mutated patients, the [...] Read more.
Inflammatory cytokines play a major role in myeloproliferative neoplasms (MPNs) as regulators of the MPN clone and as mediators of clinical symptoms and complications. Firstly, we investigated the effect of JAK2V617F on 42 molecules linked to inflammation. For JAK2V617F-mutated patients, the JAK2V617F allele burden (%JAK2V617F) correlated with the levels of IL-1β, IL-1Rα, IP-10 and leptin in polycythemia vera (PV), and with IL-33 in ET; for all other molecules, no correlation was found. Cytokine production was also studied in the human megakaryocytic cell line UT-7. Wild-type UT-7 cells secreted 27/42 cytokines measured. UT-7 clones expressing 50% or 75% JAK2V617F were generated, in which the production of IL-1β, IP-10 and RANTES was increased; other cytokines were not affected. Secondly, we searched for causes of chronic inflammation in MPNs other than driver mutations. Since antigen-driven selection is increasingly implicated in the pathogenesis of blood malignancies, we investigated whether proinflammatory glucosylsphingosine (GlcSph) may play a role in MPNs. We report that 20% (15/75) of MPN patients presented with anti-GlcSph IgGs, distinguished by elevated levels of 11 cytokines. In summary, only IL-1β and IP-10 were linked to JAK2V617F both in patients and in UT-7 cells; other inflammation-linked cytokines in excess in MPNs were not. For subsets of MPN patients, a possible cause of inflammation may be auto-immunity against glucolipids. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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15 pages, 2667 KiB  
Article
E-Cigarette Exposure Decreases Bone Marrow Hematopoietic Progenitor Cells
by Gajalakshmi Ramanathan, Brianna Craver-Hoover, Rebecca J. Arechavala, David A. Herman, Jane H. Chen, Hew Yeng Lai, Samantha R. Renusch, Michael T. Kleinman and Angela G. Fleischman
Cancers 2020, 12(8), 2292; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082292 - 14 Aug 2020
Cited by 8 | Viewed by 4226
Abstract
Electronic cigarettes (E-cigs) generate nicotine containing aerosols for inhalation and have emerged as a popular tobacco product among adolescents and young adults, yet little is known about their health effects due to their relatively recent introduction. Few studies have assessed the long-term effects [...] Read more.
Electronic cigarettes (E-cigs) generate nicotine containing aerosols for inhalation and have emerged as a popular tobacco product among adolescents and young adults, yet little is known about their health effects due to their relatively recent introduction. Few studies have assessed the long-term effects of inhaling E-cigarette smoke or vapor. Here, we show that two months of E-cigarette exposure causes suppression of bone marrow hematopoietic stem and progenitor cells (HSPCs). Specifically, the common myeloid progenitors and granulocyte-macrophage progenitors were decreased in E-cig exposed animals compared to air exposed mice. Competitive reconstitution in bone marrow transplants was not affected by two months of E-cig exposure. When air and E-cig exposed mice were challenged with an inflammatory stimulus using lipopolysaccharide (LPS), competitive fitness between the two groups was not significantly different. However, mice transplanted with bone marrow from E-cigarette plus LPS exposed mice had elevated monocytes in their peripheral blood at five months post-transplant indicating a myeloid bias similar to responses of aged hematopoietic stem cells (HSC) to an acute inflammatory challenge. We also investigated whether E-cigarette exposure enhances the selective advantage of hematopoietic cells with myeloid malignancy associated mutations. E-cigarette exposure for one month slightly increased JAK2V617F mutant cells in peripheral blood but did not have an impact on TET2−/− cells. Altogether, our findings reveal that chronic E-cigarette exposure for two months alters the bone marrow HSPC populations but does not affect HSC reconstitution in primary transplants. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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11 pages, 1179 KiB  
Article
Myelomonocytic Skewing In Vitro Discriminates Subgroups of Patients with Myelofibrosis with A Different Phenotype, A Different Mutational Profile and Different Prognosis
by Klaus Geissler, Bettina Gisslinger, Eva Jäger, Roland Jäger, Ana-Iris Schiefer, Edith Bogner, Elisabeth Fuchs, Fiorella Schischlik, Donat Alpar, Ingrid Simonitsch-Klupp, Robert Kralovics and Heinz Gisslinger
Cancers 2020, 12(8), 2291; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082291 - 14 Aug 2020
Cited by 3 | Viewed by 1672
Abstract
Normal hematopoietic function is maintained by a well-controlled balance of myelomonocytic, megaerythroid and lymphoid progenitor cell populations which may be skewed during pathologic conditions. Using semisolid in vitro cultures supporting the growth of myelomonocytic (CFU-GM) and erythroid (BFU-E) colonies, we investigated skewed differentiation [...] Read more.
Normal hematopoietic function is maintained by a well-controlled balance of myelomonocytic, megaerythroid and lymphoid progenitor cell populations which may be skewed during pathologic conditions. Using semisolid in vitro cultures supporting the growth of myelomonocytic (CFU-GM) and erythroid (BFU-E) colonies, we investigated skewed differentiation towards the myelomonocytic over erythroid commitment in 81 patients with myelofibrosis (MF). MF patients had significantly increased numbers of circulating CFU-GM and BFU-E. Myelomonocytic skewing as indicated by a CFU-GM/BFU-E ratio ≥ 1 was found in 26/81 (32%) MF patients as compared to 1/98 (1%) in normal individuals. Patients with myelomonocytic skewing as compared to patients without skewing had higher white blood cell and blast cell counts, more frequent leukoerythroblastic features, but lower hemoglobin levels and platelet counts. The presence of myelomonocytic skewing was associated with a higher frequency of additional mutations, particularly in genes of the epigenetic and/or splicing machinery, and a significantly shorter survival (46 vs. 138 mo, p < 0.001). The results of this study show that the in vitro detection of myelomonocytic skewing can discriminate subgroups of patients with MF with a different phenotype, a different mutational profile and a different prognosis. Our findings may be important for the understanding and management of MF. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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18 pages, 860 KiB  
Article
Body Mass Index and Total Symptom Burden in Myeloproliferative Neoplasms Discovery of a U-shaped Association
by Sarah Friis Christensen, Robyn Marie Scherber, Nana Brochmann, Martin Goros, Jonathan Gelfond, Christen Lykkegaard Andersen, Esben Meulengracht Flachs and Ruben Mesa
Cancers 2020, 12(8), 2202; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082202 - 06 Aug 2020
Cited by 13 | Viewed by 11320
Abstract
Elevated body mass index (BMI) is a global health problem, leading to enhanced mortality and the increased risk of several cancers including essential thrombocythemia (ET), a subtype of the Philadelphia-chromosome negative myeloproliferative neoplasms (MPN). Furthermore, evidence states that BMI is associated with the [...] Read more.
Elevated body mass index (BMI) is a global health problem, leading to enhanced mortality and the increased risk of several cancers including essential thrombocythemia (ET), a subtype of the Philadelphia-chromosome negative myeloproliferative neoplasms (MPN). Furthermore, evidence states that BMI is associated with the severity of symptom burden among cancer patients. MPN patients often suffer from severe symptom burden. The purpose of this study was to examine whether deviations from a normal BMI in an MPN population are associated with higher symptom burden and reduced quality of life (QoL). A combined analysis of two large cross-sectional surveys, the Danish Population-based Study, MPNhealthSurvey (n = 2044), and the international Fatigue Study (n = 1070), was performed. Symptoms and QoL were assessed using the validated Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). Analysis of covariance was used to estimate the effects of different BMI categories on symptom scores while adjusting for age, sex, and MPN subtype. A U-shaped association between BMI and Total Symptom Burden was observed in both datasets with significantly higher mean scores for underweight and obese patients relative to normal weight (mean difference: underweight 5.51 (25.8%), p = 0.006; obese 5.70 (26.6%) p < 0.001). This is an important finding, as BMI is a potentially modifiable factor in the care of MPN patients. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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15 pages, 2752 KiB  
Article
Mathematical Modeling of MPNs Offers Understanding and Decision Support for Personalized Treatment
by Johnny T. Ottesen, Rasmus K. Pedersen, Marc J. B. Dam, Trine A. Knudsen, Vibe Skov, Lasse Kjær and Morten Andersen
Cancers 2020, 12(8), 2119; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082119 - 30 Jul 2020
Cited by 5 | Viewed by 2949
Abstract
(1) Background: myeloproliferative neoplasms (MPNs) are slowly developing hematological cancers characterized by few driver mutations, with JAK2V617F being the most prevalent. (2) Methods: using mechanism-based mathematical modeling (MM) of hematopoietic stem cells, mutated hematopoietic stem cells, differentiated blood cells, and immune response [...] Read more.
(1) Background: myeloproliferative neoplasms (MPNs) are slowly developing hematological cancers characterized by few driver mutations, with JAK2V617F being the most prevalent. (2) Methods: using mechanism-based mathematical modeling (MM) of hematopoietic stem cells, mutated hematopoietic stem cells, differentiated blood cells, and immune response along with longitudinal data from the randomized Danish DALIAH trial, we investigate the effect of the treatment of MPNs with interferon-α2 on disease progression. (3) Results: At the population level, the JAK2V617F allele burden is halved every 25 months. At the individual level, MM describes and predicts the JAK2V617F kinetics and leukocyte- and thrombocyte counts over time. The model estimates the patient-specific treatment duration, relapse time, and threshold dose for achieving a good response to treatment. (4) Conclusions: MM in concert with clinical data is an important supplement to understand and predict the disease progression and impact of interventions at the individual level. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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10 pages, 1054 KiB  
Article
Clinical, Hematologic, Biologic and Molecular Characteristics of Patients with Myeloproliferative Neoplasms and a Chronic Myelomonocytic Leukemia-Like Phenotype
by Sonja Heibl, Bettina Gisslinger, Eva Jäger, Agnes Barna, Michael Gurbisz, Maike Stegemann, Peter Bettelheim, Sigrid Machherndl-Spandl, Michael Pfeilstöcker, Thomas Nösslinger, Gökhan Uyanik, Gregor Hoermann, Reinhard Stauder, Josef Thaler, Rajko Kusec, Peter Valent, Heinz Gisslinger and Klaus Geissler
Cancers 2020, 12(7), 1891; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071891 - 14 Jul 2020
Cited by 4 | Viewed by 2707
Abstract
Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary [...] Read more.
Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients. The hemoglobin values and platelet counts of these patients were higher than in CMML but lower than in PV, respectively. MPN/CMML patients showed myelomonocytic skewing, a typical in vitro feature of CMML but not of PV. The mutational landscape of MPN/CMML was not different from JAK2-mutated CMML. In two MPN/CMML patients, development of a CMML-like phenotype was associated with a decrease in the JAK2 V617F allelic burden. Finally, the prognosis of MPN/CMML (median overall survival (OS) 27 months) was more similar to CMML (JAK2-mutated, 28 months; JAK2-nonmutated 29 months) than to PV (186 months). In conclusion, we show that patients with MPN and a CMML-like phenotype share more characteristics with CMML than with PV, which may be relevant for their classification and clinical management. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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9 pages, 1196 KiB  
Article
Thrombotic Risk Detection in Patients with Polycythemia Vera: The Predictive Role of DNMT3A/TET2/ASXL1 Mutations
by Adrián Segura-Díaz, Ruth Stuckey, Yanira Florido, Jesús María González-Martín, Juan Francisco López-Rodríguez, Santiago Sánchez-Sosa, Elena González-Pérez, María Nieves Sáez Perdomo, María del Mar Perera, Silvia de la Iglesia, Teresa Molero-Labarta, María Teresa Gómez-Casares and Cristina Bilbao-Sieyro
Cancers 2020, 12(4), 934; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040934 - 10 Apr 2020
Cited by 37 | Viewed by 3554
Abstract
The development of thrombotic events is common among patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We studied the influence of pathogenic mutations frequently associated with myeloid malignancies on thrombotic events using next-generation sequencing (NGS) in an initial cohort [...] Read more.
The development of thrombotic events is common among patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We studied the influence of pathogenic mutations frequently associated with myeloid malignancies on thrombotic events using next-generation sequencing (NGS) in an initial cohort of 68 patients with myeloproliferative neoplasms (MPN). As expected, the presence of mutations in DNMT3A, TET2, and ASXL1 (DTA genes) was positively associated with age for the whole cohort (p = 0.025, OR: 1.047, 95% CI: 1.006–1.090). Also, while not related with events in the whole cohort, DTA mutations were strongly associated with the development of vascular events in PV patients (p = 0.028). To confirm the possible association between the presence of DTA mutation and thrombotic events, we performed a case-control study on 55 age-matched patients with PV (including 12 PV patients from the initial cohort, 25 with event vs. 30 no event). In the age-matched case-control PV cohort, the presence of ≥1 DTA mutation significantly increased the risk of a thrombotic event (OR: 6.333, p = 0.0024). Specifically, mutations in TET2 were associated with thrombotic events in the PV case-control cohort (OR: 3.56, 95% CI: 1.15–11.83, p = 0.031). Our results suggest that pathogenic DTA mutations, and particularly TET2 mutations, may be an independent risk factor for thrombosis in patients with PV. However, the predictive value of TET2 and DTA mutations in ET and PMF was inconclusive and should be determined in a larger cohort. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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Review

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14 pages, 609 KiB  
Review
Ruxolitinib-Associated Infections in Polycythemia Vera: Review of the Literature, Clinical Significance, and Recommendations
by Parvis Sadjadian, Kai Wille and Martin Griesshammer
Cancers 2020, 12(11), 3132; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113132 - 26 Oct 2020
Cited by 19 | Viewed by 4346
Abstract
Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, is approved for second-line therapy in patients with polycythemia vera (PV) who are resistant or intolerant to hydroxyurea. Due to the immunomodulatory and immunosuppressive effect of RUX, there is an increased susceptibility to infections. However, an increased risk [...] Read more.
Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, is approved for second-line therapy in patients with polycythemia vera (PV) who are resistant or intolerant to hydroxyurea. Due to the immunomodulatory and immunosuppressive effect of RUX, there is an increased susceptibility to infections. However, an increased risk of infection is inherent to even untreated myeloproliferative neoplasms (MPN). To obtain more information on the clinical significance of RUX-associated infections in PV, we reviewed the available literature. There is no evidence-based approach to managing infection risks. Most data on RUX-associated infections are available for MF. In all studies, the infection rates in the RUX and control groups were fairly similar, with the exception of infections with the varicella zoster virus (VZV). However, individual cases of bilateral toxoplasmosis retinitis, disseminated molluscum contagiosum, or a mycobacterium tuberculosis infection or a hepatitis B reactivation are reported. A careful assessment of the risk of infection for PV patients is required at the initial presentation and before the start of RUX. Screening for hepatitis B is recommended in all patients. The risk of RUX-associated infections is lower with PV than with MF, but compared to a normal population there is an increased risk of VZV infection. However, primary VZV prophylaxis for PV patients is not recommended, while secondary prophylaxis can be considered individually. As early treatment is most effective for VZV, patients should be properly informed and trained to seek medical advice immediately if cutaneous signs of VZV develop. Vaccination against influenza, herpes zoster, and pneumococci should be considered in all PV patients at risk of infection, especially if RUX treatment is planned. Current recommendations do not support adjusting or discontinuing JAK inhibition in MPN patients to reduce the risk of COVID-19. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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18 pages, 717 KiB  
Review
Risks of Solid and Lymphoid Malignancies in Patients with Myeloproliferative Neoplasms: Clinical Implications
by Mette Brabrand and Henrik Frederiksen
Cancers 2020, 12(10), 3061; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12103061 - 20 Oct 2020
Cited by 16 | Viewed by 2727
Abstract
In the past decade, several studies have reported that patients with chronic myeloproliferative neoplasms (MPNs) have an increased risk of second solid cancer or lymphoid hematological cancer. In this qualitative review study, we present results from studies that report on these cancer risks [...] Read more.
In the past decade, several studies have reported that patients with chronic myeloproliferative neoplasms (MPNs) have an increased risk of second solid cancer or lymphoid hematological cancer. In this qualitative review study, we present results from studies that report on these cancer risks in comparison to cancer incidences in the general population or a control group. Our literature search identified 12 such studies published in the period 2009–2018 including analysis of more than 65,000 patients. The results showed that risk of solid cancer is 1.5- to 3.0-fold elevated and the risk of lymphoid hematological cancer is 2.5- to 3.5-fold elevated in patients with MPNs compared to the general population. These elevated risks apply to all MPN subtypes. For solid cancers, particularly risks of skin cancer, lung cancer, thyroid cancer, and kidney cancer are elevated. The largest difference in cancer risk between patients with MPN and the general population is seen in patients below 80 years. Cancer prognosis is negatively affected due to cardiovascular events, thrombosis, and infections by a concurrent MPN diagnosis mainly among patients with localized cancer. Our review emphasizes that clinicians caring for patients with MPNs should be aware of the very well-documented increased risk of second non-myeloid cancers. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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20 pages, 2155 KiB  
Review
Novel Concepts of Treatment for Patients with Myelofibrosis and Related Neoplasms
by Prithviraj Bose, Lucia Masarova and Srdan Verstovsek
Cancers 2020, 12(10), 2891; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102891 - 09 Oct 2020
Cited by 14 | Viewed by 4856
Abstract
Janus kinase (JAK) inhibition forms the cornerstone of the treatment of myelofibrosis (MF), and the JAK inhibitor ruxolitinib is often used as a second-line agent in patients with polycythemia vera (PV) who fail hydroxyurea (HU). In addition, ruxolitinib continues to be studied in [...] Read more.
Janus kinase (JAK) inhibition forms the cornerstone of the treatment of myelofibrosis (MF), and the JAK inhibitor ruxolitinib is often used as a second-line agent in patients with polycythemia vera (PV) who fail hydroxyurea (HU). In addition, ruxolitinib continues to be studied in patients with essential thrombocythemia (ET). The benefits of JAK inhibition in terms of splenomegaly and symptoms in patients with MF are undeniable, and ruxolitinib prolongs the survival of persons with higher risk MF. Despite this, however, “disease-modifying” effects of JAK inhibitors in MF, i.e., bone marrow fibrosis and mutant allele burden reduction, are limited. Similarly, in HU-resistant/intolerant PV, while ruxolitinib provides excellent control of the hematocrit, symptoms and splenomegaly, reduction in the rate of thromboembolic events has not been convincingly demonstrated. Furthermore, JAK inhibitors do not prevent disease evolution to MF or acute myeloid leukemia (AML). Frontline cytoreductive therapy for PV generally comprises HU and interferons, which have their own limitations. Numerous novel agents, representing diverse mechanisms of action, are in development for the treatment of these three classic myeloproliferative neoplasms (MPNs). JAK inhibitor-based combinations, all of which are currently under study for MF, have been covered elsewhere in this issue. In this article, we focus on agents that have been studied as monotherapy in patients with MF, generally after JAK inhibitor resistance/intolerance, as well as several novel compounds in development for PV/ET. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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21 pages, 1842 KiB  
Review
Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms
by Steven De Almeida, Mathilde Regimbeau, Gaëtan Jego, Carmen Garrido, François Girodon and François Hermetet
Cancers 2020, 12(9), 2592; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092592 - 11 Sep 2020
Cited by 7 | Viewed by 4002
Abstract
Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce [...] Read more.
Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce MPN-related symptoms in myelofibrosis, they do not influence the underlying cause of the disease and are not curative. Due to these limitations, there is a need for alternative therapeutic strategies and targets. Heat shock proteins (HSPs) are cytoprotective stress-response chaperones involved in protein homeostasis and in many critical pathways, including inflammation. Over the last decade, several research teams have unraveled the mechanistic connection between STAT signaling and several HSPs, showing that HSPs are potential therapeutic targets for MPN. These HSPs include HSP70, HSP90 (chaperoning JAK2) and both HSP110 and HSP27, which are key factors modulating STAT3 phosphorylation status. Like the HSPs, the PD-1/PD-L1 signaling pathway has been widely studied in cancer, but the importance of PD-L1-mediated immune escape in MPN was only recently reported. In this review, we summarize the role of HSPs and PD-1/PD-L1 signaling, the modalities of their experimental blockade, and the effect in MPN. Finally, we discuss the potential of these emerging targeted approaches in MPN therapy. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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22 pages, 559 KiB  
Review
Murine Models of Myelofibrosis
by Sebastien Jacquelin, Frederike Kramer, Ann Mullally and Steven W. Lane
Cancers 2020, 12(9), 2381; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092381 - 23 Aug 2020
Cited by 12 | Viewed by 4693
Abstract
Myelofibrosis (MF) is subtype of myeloproliferative neoplasm (MPN) characterized by a relatively poor prognosis in patients. Understanding the factors that drive MF pathogenesis is crucial to identifying novel therapeutic approaches with the potential to improve patient care. Driver mutations in three main genes [...] Read more.
Myelofibrosis (MF) is subtype of myeloproliferative neoplasm (MPN) characterized by a relatively poor prognosis in patients. Understanding the factors that drive MF pathogenesis is crucial to identifying novel therapeutic approaches with the potential to improve patient care. Driver mutations in three main genes (janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL)) are recurrently mutated in MPN and are sufficient to engender MPN using animal models. Interestingly, animal studies have shown that the underlying molecular mutation and the acquisition of additional genetic lesions is associated with MF outcome and transition from early stage MPN such as essential thrombocythemia (ET) and polycythemia vera (PV) to secondary MF. In this issue, we review murine models that have contributed to a better characterization of MF pathobiology and identification of new therapeutic opportunities in MPN. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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25 pages, 323 KiB  
Review
Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis
by Andrew T. Kuykendall, Nathan P. Horvat, Garima Pandey, Rami Komrokji and Gary W. Reuther
Cancers 2020, 12(8), 2278; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082278 - 14 Aug 2020
Cited by 14 | Viewed by 3256
Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by the upregulation of the Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway with associated extramedullary hematopoiesis and a high burden of disease-related symptoms. While JAK inhibitor therapy is central to the management of [...] Read more.
Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by the upregulation of the Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway with associated extramedullary hematopoiesis and a high burden of disease-related symptoms. While JAK inhibitor therapy is central to the management of MF, it is not without limitations. In an effort to improve treatment for MF patients, there have been significant efforts to identify combination strategies that build upon the substantial benefits of JAK inhibition. Early efforts to combine agents with additive therapeutic profiles have given way to rationally designed combinations hoping to demonstrate clinical synergism and modify the underlying disease. In this article, we review the preclinical basis and existing clinical data for JAK inhibitor combination strategies while highlighting emerging strategies of particular interest. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
19 pages, 1096 KiB  
Review
Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms
by Nicolas Chatain, Steffen Koschmieder and Edgar Jost
Cancers 2020, 12(8), 2250; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082250 - 12 Aug 2020
Cited by 10 | Viewed by 4278
Abstract
Hematopoiesis is a highly regulated and complex process involving hematopoietic stem cells (HSCs), cell surface adhesion molecules, and cytokines as well as cells of the hematopoietic niche in the bone marrow (BM). Myeloproliferative neoplasms (MPNs) are characterized by clonal expansion of HSCs involving [...] Read more.
Hematopoiesis is a highly regulated and complex process involving hematopoietic stem cells (HSCs), cell surface adhesion molecules, and cytokines as well as cells of the hematopoietic niche in the bone marrow (BM). Myeloproliferative neoplasms (MPNs) are characterized by clonal expansion of HSCs involving one or more blood cell lineages. Philadelphia-negative MPNs (Ph-neg MPNs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In nearly all patients with Ph-neg MPN, mutations in the genes encoding janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL) can be detected and, together with additional mutations in epigenetic modifier genes, these genetic aberrations contribute to the clonal expansion of the cells. In addition to these intracellular changes in the malignant clone, inflammatory processes involving both the clonal and the non-clonal cells contribute to the signs and symptoms of the patients, as well as to progression of the disease to myelofibrosis (MF) or acute leukemia, and to thrombotic complications. This contribution has been corroborated in preclinical studies including mouse models and patient-derived iPS cells, and in clinical trials, using anti-inflammatory drugs such as JAK inhibitors and steroids, or immunomodulatory drugs such as IMiDs and interferon-alpha (IFNa), all of which change the (im)balance of circulating inflammatory factors (e.g., TNFa, IL-1b, and TGFβ) in MPN. Currently, allogeneic hematopoietic (stem) cell transplantation (allo-HCT) remains the only curative treatment for Ph-neg MPN and is the treatment of choice in intermediate-2 and high-risk MF. HCT can reverse inflammatory changes induced by MPN as well as fibrosis in a large proportion of patients, but it also induces itself profound changes in inflammatory cells and cytokines in the patient, which may help to eradicate the disease but also in part cause significant morbidity (e.g., by graft-versus-host disease). In this review, we focus on the contribution of aberrant inflammation to disease pathogenesis in Ph-neg MPN as well as the current understanding of its alterations after allogeneic HCT. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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22 pages, 1133 KiB  
Review
Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues
by Marie Hautin, Clélia Mornet, Aurélie Chauveau, Delphine G. Bernard, Laurent Corcos and Eric Lippert
Cancers 2020, 12(8), 2216; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082216 - 07 Aug 2020
Cited by 15 | Viewed by 4121
Abstract
Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding [...] Read more.
Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding the characterization and mechanisms of splicing anomalies in MPN. In this article, we review the current scientific literature regarding “splicing and myeloproliferative neoplasms”. We first analyse the clinical series reporting spliceosome mutations in MPN and their clinical correlates. We then present the current knowledge about molecular mechanisms by which these mutations participate in the pathogenesis of MPN or other myeloid malignancies. Beside spliceosome mutations, splicing anomalies have been described in myeloproliferative neoplasms, as well as in acute myeloid leukemias, a dreadful complication of these chronic diseases. Based on splicing anomalies reported in chronic myelogenous leukemia as well as in acute leukemia, and the mechanisms presiding splicing deregulation, we propose that abnormal splicing plays a major role in the evolution of myeloproliferative neoplasms and may be the target of specific therapeutic strategies. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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39 pages, 1292 KiB  
Review
Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses
by Vibe Skov
Cancers 2020, 12(8), 2194; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082194 - 06 Aug 2020
Cited by 25 | Viewed by 4759
Abstract
The myeloproliferative neoplasms (MPNs) are acquired hematological stem cell neoplasms characterized by driver mutations in JAK2, CALR, or MPL. Additive mutations may appear in predominantly epigenetic regulator, RNA splicing and signaling pathway genes. These molecular mutations are a hallmark of [...] Read more.
The myeloproliferative neoplasms (MPNs) are acquired hematological stem cell neoplasms characterized by driver mutations in JAK2, CALR, or MPL. Additive mutations may appear in predominantly epigenetic regulator, RNA splicing and signaling pathway genes. These molecular mutations are a hallmark of diagnostic, prognostic, and therapeutic assessment in patients with MPNs. Over the past decade, next generation sequencing (NGS) has identified multiple somatic mutations in MPNs and has contributed substantially to our understanding of the disease pathogenesis highlighting the role of clonal evolution in disease progression. In addition, disease prognostication has expanded from encompassing only clinical decision making to include genomics in prognostic scoring systems. Taking into account the decreasing costs and increasing speed and availability of high throughput technologies, the integration of NGS into a diagnostic, prognostic and therapeutic pipeline is within reach. In this review, these aspects will be discussed highlighting their role regarding disease outcome and treatment modalities in patients with MPNs. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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21 pages, 1269 KiB  
Review
Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms
by Lasse Kjær
Cancers 2020, 12(8), 2100; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082100 - 28 Jul 2020
Cited by 17 | Viewed by 3579
Abstract
Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia [...] Read more.
Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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15 pages, 1310 KiB  
Review
Impact of Host, Lifestyle and Environmental Factors in the Pathogenesis of MPN
by Gajalakshmi Ramanathan, Brianna M Hoover and Angela G Fleischman
Cancers 2020, 12(8), 2038; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082038 - 24 Jul 2020
Cited by 8 | Viewed by 5423
Abstract
Philadelphia-negative myeloproliferative neoplasms (MPNs) occur when there is over-production of myeloid cells stemming from hematopoietic stem cells with constitutive activation of JAK/STAT signaling, with JAK2V617F being the most commonly occurring somatic driver mutation. Chronic inflammation is a hallmark feature of MPNs and [...] Read more.
Philadelphia-negative myeloproliferative neoplasms (MPNs) occur when there is over-production of myeloid cells stemming from hematopoietic stem cells with constitutive activation of JAK/STAT signaling, with JAK2V617F being the most commonly occurring somatic driver mutation. Chronic inflammation is a hallmark feature of MPNs and it is now evident that inflammation is not only a symptom of MPN but can also provoke development and precipitate progression of disease. Herein we have considered major MPN driver mutation independent host, lifestyle, and environmental factors in the pathogenesis of MPN based upon epidemiological and experimental data. In addition to the traditional risk factors such as advanced age, there is evidence to indicate that inflammatory stimuli such as smoking can promote and drive MPN clone emergence and expansion. Diet induced inflammation could also play a role in MPN clonal expansion. Recognition of factors associated with MPN development support lifestyle modifications as an emerging therapeutic tool to restrain inflammation and diminish MPN progression. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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13 pages, 255 KiB  
Review
Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature
by Joan How and Gabriela Hobbs
Cancers 2020, 12(7), 1954; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071954 - 18 Jul 2020
Cited by 36 | Viewed by 6838
Abstract
Interferon alfa was first used in the treatment of myeloproliferative neoplasms (MPNs) over 30 years ago. However, its initial use was hampered by its side effect profile and lack of official regulatory approval for MPN treatment. Recently, there has been renewed interest in [...] Read more.
Interferon alfa was first used in the treatment of myeloproliferative neoplasms (MPNs) over 30 years ago. However, its initial use was hampered by its side effect profile and lack of official regulatory approval for MPN treatment. Recently, there has been renewed interest in the use of interferon in MPNs, given its potential disease-modifying effects, with associated molecular and histopathological responses. The development of pegylated formulations and, more recently, ropeginterferon alfa-2b has resulted in improved tolerability and further expansion of interferon’s use. We review the evolving clinical use of interferon in essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). We discuss interferon’s place in MPN treatment in the context of the most recent clinical trial results evaluating interferon and its pegylated formulations, and its role in special populations such as young and pregnant MPN patients. Interferon has re-emerged as an important option in MPN patients, with future studies seeking to re-establish its place in the existing treatment algorithm for MPN, and potentially expanding its use for novel indications and combination therapies. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
11 pages, 267 KiB  
Review
Aetiology of Myeloproliferative Neoplasms
by Mary Frances McMullin and Lesley Ann Anderson
Cancers 2020, 12(7), 1810; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071810 - 06 Jul 2020
Cited by 16 | Viewed by 3677
Abstract
Myeloproliferative neoplasms (MPNs) have estimated annual incidence rates for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis of 0.84, 1.03, and 0.47 per 100,000. Prevalence is much higher, particularly for PV and ET, as mortality rates are relatively low. Patients are often [...] Read more.
Myeloproliferative neoplasms (MPNs) have estimated annual incidence rates for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis of 0.84, 1.03, and 0.47 per 100,000. Prevalence is much higher, particularly for PV and ET, as mortality rates are relatively low. Patients are often concerned about why they developed an MPN and epidemiological studies enable the identification of potential causative factors. Previous work in small heterogeneous studies has identified a variety of risk factors associated with MPNs including family history of MPN, autoimmune conditions, some occupational exposures, and blood donation. At a population level, germline predisposition factors in various populations have been associated with MPNs. The pilot MOSAICC (Myeloproliferative Neoplasm: An In-depth Case-Control) study is one of the largest epidemiological studies in MPN ever carried out to date. It demonstrated the most effective methods for carrying out a significant epidemiological study in this patient group including the best way of recruiting controls, as well as how to evaluate occupational and lifestyle exposures, evaluate symptoms, and collect biological samples. Significant results linked to MPNs in the pilot study of 106 patients included smoking, obesity, and childhood socioeconomic status. The methodology is now in place for a much larger ongoing MOSAICC study which should provide further insight into the potential causes of MPNs. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
21 pages, 2114 KiB  
Review
Cancer Immune Therapy for Philadelphia Chromosome-Negative Chronic Myeloproliferative Neoplasms
by Morten Orebo Holmström, Hans Carl Hasselbalch and Mads Hald Andersen
Cancers 2020, 12(7), 1763; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071763 - 02 Jul 2020
Cited by 17 | Viewed by 3218
Abstract
Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) are neoplastic diseases of the hematopoietic stem cells in the bone marrow. MPN are characterized by chronic inflammation and immune dysregulation. Of interest, the potent immunostimulatory cytokine interferon-α has been used to treat MPN for decades. A [...] Read more.
Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) are neoplastic diseases of the hematopoietic stem cells in the bone marrow. MPN are characterized by chronic inflammation and immune dysregulation. Of interest, the potent immunostimulatory cytokine interferon-α has been used to treat MPN for decades. A deeper understanding of the anti-cancer immune response and of the different immune regulatory mechanisms in patients with MPN has paved the way for an increased perception of the potential of cancer immunotherapy in MPN. Therapeutic vaccination targeting the driver mutations in MPN is one recently described potential new treatment modality. Furthermore, T cells can directly react against regulatory immune cells because they recognize proteins like arginase and programmed death ligand 1 (PD-L1). Therapeutic vaccination with arginase or PD-L1 therefore offers a novel way to directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens like mutant CALR and mutant JAK2. Other therapeutic options that could be used in concert with therapeutic cancer vaccines are immune checkpoint–blocking antibodies and interferon-α. For more advanced MPN, adoptive cellular therapy is a potential option that needs more preclinical investigation. In this review, we summarize current knowledge about the immune system in MPN and discuss the many opportunities for anti-cancer immunotherapy in patients with MPN. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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19 pages, 1084 KiB  
Review
Essential Thrombocythemia and Acquired von Willebrand Syndrome: The Shadowlands between Thrombosis and Bleeding
by Hassan Awada, Maria Teresa Voso, Paola Guglielmelli and Carmelo Gurnari
Cancers 2020, 12(7), 1746; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071746 - 30 Jun 2020
Cited by 19 | Viewed by 7921
Abstract
Over the past decade, new insights have emerged on the pathophysiology of essential thrombocythemia (ET), its clinical management, and associated thrombohemostatic disturbances. Here, we review the latest diagnostic and risk stratification modalities of ET and its therapeutics. Moreover, we discuss the clinical evidence-based [...] Read more.
Over the past decade, new insights have emerged on the pathophysiology of essential thrombocythemia (ET), its clinical management, and associated thrombohemostatic disturbances. Here, we review the latest diagnostic and risk stratification modalities of ET and its therapeutics. Moreover, we discuss the clinical evidence-based benefits, deriving from major clinical trials, of using cytoreductive therapy and antiplatelet agents to lower the risk of fatal vascular events. Also, we focus on the condition of extreme thrombocytosis (>1000 × 109/L) and bleeding risk, the development and pathogenesis of acquired von Willebrand syndrome, and the clinical approach to this paradoxical scenario in ET. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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14 pages, 609 KiB  
Review
Ocular Manifestations in Patients with Philadelphia-Negative Myeloproliferative Neoplasms
by Charlotte Liisborg, Hans Carl Hasselbalch and Torben Lykke Sørensen
Cancers 2020, 12(3), 573; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030573 - 02 Mar 2020
Cited by 13 | Viewed by 4488
Abstract
The major complications of Philadelphia-negative (Ph-Negative) myeloproliferative neoplasms (MPNs) are thrombosis, haemorrhage and leukemic transformation. As systemic and haematological diseases, MPNs have the potential to affect many tissues and organs. Some complications lead to the diagnosis of MPNs, but other signs and symptoms [...] Read more.
The major complications of Philadelphia-negative (Ph-Negative) myeloproliferative neoplasms (MPNs) are thrombosis, haemorrhage and leukemic transformation. As systemic and haematological diseases, MPNs have the potential to affect many tissues and organs. Some complications lead to the diagnosis of MPNs, but other signs and symptoms are often misdiagnosed or neglected as a sign of MPN disease. Therefore, we reviewed the current literature to investigate and delineate the clinical manifestations seen in the eyes of Ph-negative MPN patients. We found that ocular manifestations are common among patients with MPNs. The most frequently described manifestations are due to the consequences of haematological abnormalities causing microvascular disturbances and hyperviscosity. More serious and vision-threatening complications as thrombotic events in the eyes have been repeatedly reported as well. These ocular symptoms may precede more serious extraocular complications. Accordingly, combined ophthalmological and haematological management have the potential to discover these diseases earlier and prevent morbidity and mortality in these patients. Furthermore, routine ophthalmological screening of all newly diagnosed MPN patients may be a preventive approach for early diagnosis and timely treatment of the ocular manifestations. Full article
(This article belongs to the Special Issue New Insights into Myeloproliferative Neoplasms)
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