Janus kinase inhibitors: jackpot or potluck?

The reports of a unique mutation in the Janus kinase-2 gene (<em>JAK2</em>) in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN): primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

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Janus kinase inhibitors: jackpot or potluck?

Oncology Reviews ◽

10.4081/oncol.2012.187 ◽

2012 ◽

pp. e13

Author(s):

Pavithran Keechilat ◽

Shripad Brahmanand Pande

Keyword(s):

High Risk ◽

Polycythemia Vera ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Janus Kinase ◽

Current Evidence ◽

Federal Drug Administration ◽

Janus Kinase Inhibitors

The reports of a unique mutation in the Janus kinase-2 gene (JAK2) in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN): primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

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Clinical management of Lupus patients during the COVID-19 pandemic

Lupus ◽

10.1177/0961203320961848 ◽

2020 ◽

Vol 29 (13) ◽

pp. 1661-1672

Author(s):

Alice Mason ◽

Emily Rose ◽

Christopher J Edwards

Keyword(s):

Kinase Inhibitors ◽

Viral Infections ◽

Positive Impact ◽

Severe Disease ◽

Social Contact ◽

Janus Kinase ◽

Current Evidence ◽

Janus Kinase Inhibitors ◽

Huge Impact

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), the virus causing Coronavirus disease 2019 (COVID-19), has had a huge impact on health services with a high mortality associated with complications including pneumonia and acute respiratory distress syndrome. Historical evidence suggests that Lupus patients have a higher incidence of several viral infections. This is likely due to a combination of immune dysfunction, immunosuppressive therapy and excess co-morbidities. In this context there has been concern that Lupus patients may be at a higher risk of developing COVID-19 and suffering a severe disease course. As a result, many Lupus patients have been advised to ‘shield’ by isolating from social contact in the hope that this will reduce the likelihood of infection. Early clinical data does not appear to show that the incidence of COVID-19 is higher in Lupus patients. Reassuringly, the clinical course of COVID-19 in Lupus does not generally seem to be more severe than in the general population. There has been huge interest in repurposing existing drugs as potential treatments, including several used to treat Lupus. Of these, corticosteroids and hydroxychloroquine are the most well researched so far. The current evidence suggests that the corticosteroid dexamethasone improves outcome for the sickest COVID-19 patients requiring respiratory support. Initial reports suggested that hydroxychloroquine could have a positive impact on the course of COVID-19, however larger prospective studies have not supported this. Janus kinase inhibitors, currently being investigated for efficacy in lupus, have been shown to have anti-viral effects in vitro and inhibiting the JAK-STAT pathway may dampen down the host hyper-inflammatory response. Several trials are ongoing to assess the outcome of the use of JAK inhibitors in COVID-19 positive patients. For most patients continuing with their existing therapies to prevent a lupus flare or adverse events associated with sudden corticosteroid withdrawal is important whilst an Individualised risk assessment remains vital.

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Reducing symptom burden in patients with myeloproliferative neoplasms in the era of Janus kinase inhibitors

Leukemia & Lymphoma ◽

10.3109/10428194.2014.983098 ◽

2015 ◽

Vol 56 (7) ◽

pp. 1989-1999 ◽

Cited By ~ 17

Author(s):

Ruben A. Mesa ◽

Robyn M. Scherber ◽

Holly L. Geyer

Keyword(s):

Kinase Inhibitors ◽

Myeloproliferative Neoplasms ◽

Symptom Burden ◽

Janus Kinase ◽

Janus Kinase Inhibitors

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JAK-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

10.21203/rs.3.rs-64782/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lucas Walz ◽

Avi J. Cohen ◽

Andre P. Rebaza ◽

James Vanchieri ◽

Martin D. Slade ◽

...

Keyword(s):

Clinical Outcomes ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Type I Interferon ◽

Meta Analysis ◽

Janus Kinase ◽

Type I Interferons ◽

Type I ◽

Janus Kinase Inhibitor ◽

Janus Kinase Inhibitors

Abstract Background The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 17 million. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and due to direct antiviral ability against viruses including coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate the effect of Janus kinase-inhibitors and Type I interferons and their ability to produce positive patient outcomes in COVID-19 patients. Methods A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30 th 2020, including any study type that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan. Results Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03 – 0.39, p<0.001) and ICU admission (OR, 0.05; 95% CI, 0.01 – 0.26, p<0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68 – 48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04 – 0.85, p<0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00 – 3.59, p=0.05). Conclusions Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.

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Monitoring efforts in myeloproliferative neoplasms

Oxford Specialist Handbook: Myeloproliferative Neoplasms ◽

10.1093/med/9780198744214.003.0015 ◽

2020 ◽

pp. 234-248

Author(s):

Daniel Egan ◽

Jerald P. Radich

Keyword(s):

Tyrosine Kinase ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

Jak2 V617f ◽

Primary Myelofibrosis ◽

Polycythaemia Vera ◽

Mrna Levels ◽

Tyrosine Kinase Inhibitor Therapy

Targeted therapy with tyrosine kinase inhibitors (TKI) has transformed the therapy of chronic myeloid leukaemia (CML), and is increasingly playing a role in the management of the myeloproliferative neoplasms (MPN), as a whole. In CML, the Philadelphia chromosome drives disease pathogenesis, and is the basis of both therapy (aimed at the BCR-ABL protein) and monitoring (the BCR-ABL chimeric mRNA). The efficacy of tyrosine kinase inhibitor therapy in CML is now accessed by reaching treatment milestones based on the BCR-ABL mRNA levels. In MPN, the landscape of genetic mutations associated with essential thrombocytosis (ET), polycythaemia vera (PV), and primary myelofibrosis (PMF) is ongoing. However, the recent discoveries of the JAK2 V617F and calreticulin mutations (for example) have a similar potential for disease targeting and monitoring as in CML.

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Cementless bipolar hemiarthroplasty in a patient with PMF: a case report

Journal of Surgical Case Reports ◽

10.1093/jscr/rjz274 ◽

2019 ◽

Vol 2019 (11) ◽

Author(s):

Abdullah A Alturki ◽

Nayf A Alshammari ◽

Firas M Alsebayel ◽

Ali A Alhandi

Keyword(s):

Kinase Inhibitor ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Janus Kinase ◽

Bipolar Hemiarthroplasty ◽

Myeloproliferative Disease ◽

Neck Of Femur ◽

Janus Kinase Inhibitor ◽

History Of ◽

Neck Of Femur Fracture

Abstract Myelofibrosis is a myeloproliferative disease that falls under a group of bone marrow malignancies known as myeloproliferative neoplasms. It manifests with splenomegaly, anemia, leukocytosis and, less commonly, bone pain. Ruxolitinib, Janus kinase inhibitor, has been shown to increase survival, to improve symptoms and has the potential to decrease osteosclerotic changes. Herein, we present a case of primary myelofibrosis (PMF) in a 60-year-old female who presented with 8-month history of progressive left hip pain and later was diagnosed with pathological neck of femur fracture that was treated with cementless hemiarthroplasty. In conclusion, the use of cementless implants in hip arthroplasty in the presence of PMF has shown to be an effective and safe choice.

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Janus kinase inhibitors for the treatment of myeloproliferative neoplasms

Expert Opinion on Pharmacotherapy ◽

10.1517/14656566.2014.913024 ◽

2014 ◽

Vol 15 (9) ◽

pp. 1265-1276 ◽

Cited By ~ 24

Author(s):

Allison Rosenthal ◽

Ruben A Mesa

Keyword(s):

Kinase Inhibitors ◽

Myeloproliferative Neoplasms ◽

Janus Kinase ◽

Janus Kinase Inhibitors

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Janus kinase inhibitors may be an effective treatment to reduce skin depigmentation in vitiligo

Clinical Research in Practice The Journal of Team Hippocrates ◽

10.22237/crp/1593561900 ◽

2020 ◽

Vol 6 (2) ◽

Author(s):

Shannon E Lohman

Keyword(s):

Effective Treatment ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Clinical Decision ◽

Janus Kinase ◽

Janus Kinase Inhibitor ◽

Janus Kinase Inhibitors

A clinical decision report appraising Rothstein B, Joshipura D, Saraiya A, Abdat R, Ashkar H, Turkowski Y, Sheth V, Huang V, Au SC, Kachuk C, Dumont N, Gottlieb AB, Rosmarin D. Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib. J Am Acad Dermatol.2017 Jun;76(6):1054-1060.e1. https://doi.org/10.1016/j.jaad.2017.02.049 for a patient with worsening vitiligo.

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