Ruxolitinib-Associated Infections in Polycythemia Vera: Review of the Literature, Clinical Significance, and Recommendations

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.

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Thrombocytosis: Diagnostic Evaluation, Thrombotic Risk Stratification, and Risk-Based Management Strategies

Thrombosis ◽

10.1155/2011/536062 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 43

Author(s):

Jonathan S. Bleeker ◽

William J. Hogan

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasms ◽

Treatment Options ◽

Treatment Strategies ◽

Diagnostic Evaluation ◽

Diagnostic Process ◽

Special Focus ◽

Thrombotic Risk ◽

Increased Risk

Thrombocytosis is a commonly encountered clinical scenario, with a large proportion of cases discovered incidentally. The differential diagnosis for thrombocytosis is broad and the diagnostic process can be challenging. Thrombocytosis can be spurious, attributed to a reactive process or due to clonal disorder. This distinction is important as it carries implications for evaluation, prognosis, and treatment. Clonal thrombocytosis associated with the myeloproliferative neoplasms, especially essential thrombocythemia and polycythemia vera, carries a unique prognostic profile, with a markedly increased risk of thrombosis. This risk is the driving factor behind treatment strategies in these disorders. Clinical trials utilizing targeted therapies in thrombocytosis are ongoing with new therapeutic targets waiting to be explored. This paper will outline the mechanisms underlying thrombocytosis, the diagnostic evaluation of thrombocytosis, complications of thrombocytosis with a special focus on thrombotic risk as well as treatment options for clonal processes leading to thrombocytosis, including essential thrombocythemia and polycythemia vera.

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The Prevalence of Hepatitis B Infection in Adults with no Recognized Increased Risk of Infection

Journal of Infection ◽

10.1053/jinf.2000.0722 ◽

2000 ◽

Vol 41 (2) ◽

pp. 198-199 ◽

Cited By ~ 7

Author(s):

K. Soldan ◽

N.J. Gay ◽

J.P. Allain ◽

C. Llewelyn ◽

C. Jones ◽

...

Keyword(s):

Hepatitis B ◽

Hepatitis B Infection ◽

Risk Of Infection ◽

Increased Risk

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Leukocytosis Can Predict Thrombotic Events in Myelofibrosis

Blood ◽

10.1182/blood.v126.23.5191.5191 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5191-5191

Author(s):

Laura Coutinho Vassalli ◽

Emilia Carolina Malafaia ◽

Maria L. Chauffaille ◽

Daniella Kerbauy

Keyword(s):

Polycythemia Vera ◽

Blood Cells ◽

Myeloproliferative Neoplasms ◽

Thrombotic Event ◽

White Blood Cells ◽

Jak2 V617f ◽

The Other ◽

Jak2 V617f Mutation ◽

Increased Risk ◽

V617f Mutation

Abstract Thrombotic events are the main complication of Philadelphia-negative chronic myeloproliferative neoplasms (MPN). In polycythemia vera (PV) and essential thrombocythemia (ET), risk factors for thrombosis are well established, such as age greater than 60 years and previous thrombosis. However, the role of JAK2 V617F mutation and leukocytosis at diagnosis as risk factor for thrombosis is still controversial. Our aim was to identify factors related to the risk for thrombotic events in the studied population.This study is a retrospective non-interventional cohort. All of the analyses were performed using the database of 142 patients with MPN regularly followed at the Hematology Division (at UNIFESP-SP) from 1992 to 2014. Diagnosis was established according to WHO criteria. We analyzed the JAK2 V617F mutation, hemoglobin (g/dL), hematocrit (%), white blood cells (x109/L) and platelets (x109/L) at the diagnosis and DIPSS-Plus risk score (International Working Group for Myelofibrosis Research and Treatment, 2009). These variables were associated with thrombotic event at any time.Of the 142 patients, 54 had diagnosis of PMF, 28 of PV, 33 of ET and 27 of post-essential thrombocythaemic myelofibrosis (post ET MF) or post-polycythaemic myelofibrosis (post-PV MF). This last group was included in myelofibrosis group for statistical purposes. Thrombotic events were more frequent in PV patients (39.2%), followed by ET (33.3%), and PMF (20.9%). From those which JAK2 mutation was obtained, it was positive in 92.4% of PV patients, 62% of PMF and 50% of ET. In none of the three groups, the presence of JAK2 V617F mutation was related to increased risk of thrombosis. In myelofibrosis, leukocytosis was higher among thrombotic patients (median of 13.7 in thrombotic group versus 9.7x 109/L; p 0.0379). None of the other parameters, hemoglobin, hematocrit, platelets and DIPSS-Plus were statistically significant. In ET, the hemoglobin level at diagnosis was significantly higher in the presence of thrombosis (mean of 14.57 in thrombotic group against 13.03 g/dL in the non-thrombotic one, p 0.0428). The other parameters, hematocrit, white blood cells and platelets were not relevant. The median WBC in the thrombotic group was 9.4 and in the non-thrombotic one 9.3 x109/L. Finally, in polycythemia vera, none of the variables were related to thrombosis. Among the studied population, leukocytosis was increased in patients with thrombotic event in MF. Thus, monitoring leukocyte count in MF is essential to predict thrombosis risk and should be further studied in order to define therapeutic goals in these patients. Disclosures No relevant conflicts of interest to declare.

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Vaccination Induced Immunity to the Hepatitis B Virus among High-Risk Groups in Glasgow 1993–2001: Evaluating the Effectiveness of the United Kingdom's Selective Immunisation Policy

Scottish Medical Journal ◽

10.1258/rsmsmj.53.4.13 ◽

2008 ◽

Vol 53 (4) ◽

pp. 13-17 ◽

Cited By ~ 4

Author(s):

KM Roy ◽

DJ Goldberg ◽

K Wilson ◽

SO Cameron

Keyword(s):

High Risk ◽

Hepatitis B ◽

Drug Users ◽

Close Contact ◽

Risk Groups ◽

Hbv Infection ◽

Risk Of Infection ◽

Selective Approach ◽

Hiv Test ◽

Increased Risk

Background and Aims The United Kingdom has adopted a selective approach to the control of hepatitis B (HBV), vaccinating those at increased risk of infection through lifestyle, occupation or other factors such as close contact with a case or carrier. This paper sought to assess the effectiveness of the targeted HBV vaccination programme, by determining the level of immunity and exposure to HBV infection among three high risk groups (injecting drug users (IDUs), men who have sex with men (MSM) and heterosexuals attending genitourinary medicine clinics) at three time points between 1993–2001 in Glasgow, Scotland. Methods Residual sera from i) IDUs having a named HIV test and ii) MSM and heterosexual men and women attending GUM clinics and undergoing routine syphilis serology testing, were tested anonymously for HBV infection. Results The overall prevalence of HBV infection remained at a low level in all three risk groups. IDUs continue to be the group at greatest risk of infection. Discussion Despite the implementation of new initiatives targeting high-risk groups, vaccination levels remain low in the populations studied.

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Philadelphia-Negative Chronic Myeloproliferative Neoplasms during the COVID-19 Pandemic: Challenges and Future Scenarios

Cancers ◽

10.3390/cancers13194750 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4750

Author(s):

Francesca Palandri ◽

Massimo Breccia ◽

Valerio De Stefano ◽

Francesco Passamonti

Keyword(s):

Hematological Malignancies ◽

Myeloproliferative Neoplasms ◽

Published Data ◽

Future Scenarios ◽

Risk Of Infection ◽

Immunosuppressive Activity ◽

Chronic Myeloproliferative Neoplasms ◽

Increased Risk ◽

Abrupt Discontinuation ◽

Case Basis

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) started in December 2019 in China and then become pandemic in February 2020. Several publications investigated the possible increased rate of COVID-19 infection in hematological malignancies. Based on the published data, strategies for the management of chronic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are provided. The risk of severe COVID-19 seems high in MPN, particularly in patients with essential thrombocythemia, but not negligible in myelofibrosis. MPN patients are at high risk of both thrombotic and hemorrhagic complications and this must be accounted in the case of COVID-19 deciding on a case-by-case basis. There are currently no data to suggest that hydroxyurea or interferon may influence the risk or severity of COVID-19 infection. Conversely, while the immunosuppressive activity of ruxolitinib might pose increased risk of infection, its abrupt discontinuation during COVID-19 syndrome is associated with worse outcome. All MPN patients should receive vaccine against COVID-19; reassuring data are available on efficacy of mRNA vaccines in MPNs.

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Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24 577 first-degree relatives of 11 039 patients with myeloproliferative neoplasms in Sweden

Blood ◽

10.1182/blood-2008-03-143602 ◽

2008 ◽

Vol 112 (6) ◽

pp. 2199-2204 ◽

Cited By ~ 146

Author(s):

Ola Landgren ◽

Lynn R. Goldin ◽

Sigurdur Y. Kristinsson ◽

Elin A. Helgadottir ◽

Jan Samuelsson ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloid Leukemia ◽

Myeloproliferative Neoplasms ◽

Familial Aggregation ◽

Susceptibility Gene ◽

Degree Relative ◽

First Degree Relatives ◽

Relative Risks ◽

Increased Risk

Abstract Previous small studies have reported familial clustering of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We identified 6217 PV, 2838 ET, 1172 MF, and 812 MPN unclassifiable (NOS) patients diagnosed in Sweden, 43 550 controls, and first-degree relatives of cases (n = 24 577) and controls (n = 99 542). Using a marginal survival model, we calculated relative risks (RRs) and 95% confidence intervals as measures of familial aggregation. Relatives of MPN patients had significantly increased risks of PV (RR = 5.7; 3.5-9.1), ET (RR = 7.4; 3.7-14.8), and MPN NOS (RR = 7.5; 2.7-20.8). Analyses stratified by type of first-degree relative revealed consistently higher risks for siblings, compatible with a model of recessive genetic inheritance, which can be confirmed only by identifying the susceptibility gene(s). Mean age at MPN diagnosis was not different (P = .20) for affected relatives of cases (57.5 years) versus controls (60.6 years), and risk of MPN by age was not different for parents versus offspring of MPN cases (P = .10), providing no support for anticipation. Relatives of MPN patients had a borderline increased risk of chronic myeloid leukemia (CML; RR = 1.9; 0.9-3.8; P = .09). Our findings of 5- to 7-fold elevated risk of MPNs among first-degree relatives of MPN patients support the hypothesis that common, strong, shared susceptibility genes predispose to PV, ET, MF, and possibly CML.

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JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients

Blood ◽

10.1182/blood-2011-02-339655 ◽

2011 ◽

Vol 118 (9) ◽

pp. 2599-2601 ◽

Cited By ~ 43

Author(s):

Marina Panova-Noeva ◽

Marina Marchetti ◽

Sabrina Buoro ◽

Laura Russo ◽

Annamaria Leuzzi ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasms ◽

Jak2v617f Mutation ◽

Favorable Effect ◽

Thrombotic Risk ◽

Mutational Status ◽

Hydroxyurea Treatment ◽

Increased Risk ◽

Hydroxyurea Therapy

Abstract Immature platelets (IPFs), which are hemostatically more active than mature platelets, have been found elevated in essential thrombocythemia and polycythemia vera, 2 myeloproliferative neoplasms (MPN) characterized by an increased risk of thrombosis. It is not known whether the IPF levels are influenced by pathogenetic factors, including JAK2V617F mutational status, or by treatment regimen. To address this point, in 46 essential thrombocythemia and 38 polycythemia vera consecutive patients, we measured IPF and correlated the results to JAK2V617F mutation and myelosuppressive treatment with hydroxyurea. This analysis provides 2 new elements regarding IPF and MPN. The first finding is that the JAK2V617F mutation is linked to the quantity of IPF in patients with MPN, which might contribute to the prothrombotic phenotype in these patients. The second finding is that IPF is susceptible to myelosuppressive treatment, which may additionally explain the favorable effect of hydroxyurea therapy on MPN outcome as well as the associated thrombotic risk.

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The prevalence of hepatitis B infection in adults in England and Wales

Epidemiology and Infection ◽

10.1017/s0950268898001745 ◽

1999 ◽

Vol 122 (1) ◽

pp. 133-138 ◽

Cited By ~ 29

Author(s):

N. J. GAY ◽

L. M. HESKETH ◽

K. P. OSBORNE ◽

C. P. FARRINGTON ◽

P. MORGAN-CAPNER ◽

...

Keyword(s):

Hepatitis B ◽

Hepatitis B Vaccination ◽

Country Of Birth ◽

Risk Of Infection ◽

Robust Estimate ◽

England And Wales ◽

Prevalence Studies ◽

Increased Risk ◽

The Uk ◽

Low Prevalence

Cost effectiveness analyses of alternative hepatitis B vaccination programmes in England and Wales require a robust estimate of the lifetime risk of carriage. To this end, we report the prevalence of infection in 3781 anonymized individuals aged 15–44 years whose sera were submitted in 1996 to 16 microbiology laboratories in England and Wales. One hundred and forty-six individuals (3·9%) were confirmed as anti HBc positive, including 14 chronic carriers (0·37%). The prevalence of infection and carriage was higher in samples collected in London and increased with age. No increased risk of infection was seen in sera from genito-urinary (GUM) clinics. Only 15 sera positive for hepatitis B were also positive for hepatitis C. Our results confirm the low prevalence of hepatitis B in England and Wales, are consistent with previous estimates of carriage and suggest that many infections were acquired while resident outside the UK. Future prevalence studies should determine the country of birth and other risk factors for each individual in order to confirm these findings.

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Management of symptoms in polycythemia vera and essential thrombocythemia patients

Hematology ◽

10.1182/asheducation-2015.1.340 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 340-348 ◽

Cited By ~ 5

Author(s):

Deepti Radia ◽

Holly L. Geyer

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasms ◽

Treatment Strategies ◽

Symptom Burden ◽

Symptom Assessment ◽

Therapeutic Interventions ◽

Full Blood Count ◽

Increased Risk ◽

The Impact

Abstract The BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal stem cell derived malignancies, which include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). The MPNs are characterized by dysregulated JAK-STAT signaling pathways. PV and ET are associated with an increased risk of thrombo-hemorrhagic complications, risk of progression to MF and leukemia. Presentation of patients with PV and ET is variable and usually as a result of abnormal full blood count indices (raised hemoglobin and hematocrit, leukocytosis, and thrombocytosis). Presentation with thrombosis or splenomegaly occurs in ∼30% of patients. Historically thought of as indolent compared with MF, patients with PV and ET have significant disease symptom burden which does not directly correlate to the current clinical prognostic classifications. The mainstay of therapy is reserved for patients with high-risk disease and thus excludes a population of patients with significant symptom related morbidity impacting their quality-of-life and survival. Recent treatment strategies have aimed to incorporate disease burden assessment into the selection of therapeutic interventions such as JAK2 inhibitors and HDAC inhibitors. We will review the advances in the field of MPN symptom assessment and symptom burden experienced by ET and PV patients. We will also discuss the risk-stratified management of ET and PV patients alongside symptom assessment and the impact of potential novel therapies, for patients who fail to respond to conventional treatment.

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How I Manage Thrombotic/Thromboembolic Complications in Myeloproliferative Neoplasms

Hämostaseologie ◽

10.1055/s-0040-1701474 ◽

2020 ◽

Vol 40 (01) ◽

pp. 047-053

Author(s):

Steffen Koschmieder

Keyword(s):

Venous Thrombosis ◽

Myeloproliferative Neoplasms ◽

Normal Population ◽

Antiplatelet Agents ◽

Bleeding Risk ◽

Primary Myelofibrosis ◽

Severe Bleeding ◽

Vein Thrombosis ◽

Increased Risk ◽

The Individual

AbstractPatients with myeloproliferative neoplasms (MPNs), such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are at increased risk for arterial and venous thrombosis/thromboembolism. In particular, the risk of splanchnic venous thrombosis, such as portal vein thrombosis or Budd–Chiari syndrome, is significantly higher in patients with MPN than in the normal population. At the same time, MPN patients are at increased risk for severe bleeding. Therefore, the treatment of patients with MPN must be based on their suspected probability of thrombosis/thromboembolism and bleeding. For this purpose, patient and MPN-specific risk factors are used. Patients at expected high risk of thrombosis should receive adequate primary or secondary thromboprophylaxis in addition to cytoreductive therapy. This may consist of antiplatelet agents and/or anticoagulant agents and must be balanced with the individual bleeding risk. The goal is to increase the quality of life and life span of patients with MPNs by preventing (re-)thrombosis and severe bleeding.

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