Specificity of JAK-kinase inhibition determines impact on human and murine T-cell function

Perner, Florian; Schnöder, Tina M.; Ranjan, Satish; Wolleschak, Denise; Ebert, Caroline; Pils, Marina C.; Frey, Stephanie; Polanetzki, Anja; Fahldieck, Corinna; Schönborn, U; Schraven, Burkhart; Isermann, Berend; Fischer, Thomas

doi:10.1038/leu.2015.218

Cited by 22 publications

(28 citation statements)

References 14 publications

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“…The question how the type of pharmacologic treatment, the MPN subtype or the disease stage may influence the risk for infectious complications remains still unclear. Immunosuppressive effects of JAK inhibitors are determined by their specificity [4], while other cytoreductive agents such as hydroxycarbamide or interferons may also compromise the function of immune cells. Finally, molecular and clinical heterogeneity of MPN, its impact on cellular signaling, immune function and the inflammatory phenotype may vary depending on the type of driver mutation and disease burden [5,6].…”

Section: To the Editormentioning

confidence: 99%

Frequency of infections in 948 MPN patients: a prospective multicenter patient-reported pilot study

et al. 2020

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Section: To the Editormentioning

confidence: 99%

Frequency of infections in 948 MPN patients: a prospective multicenter patient-reported pilot study

et al. 2020

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“…These three groups collectively confirm reductions in the Treg population following exposure to both ruxolitinib and also, in the work by Keohane et al, fedratinib. More recently, Perner et al performed preliminary investigations to ascertain if the specificity of JAK inhibition determined these apparently pleotropic immunomodulatory effects on the T cell population [66]. Both momelotinib and ruxolitinib (agents inhibiting JAK1/ 2 in the low nanomolar range) reduced markers of T cell activation and inhibited T cell proliferation in vitro.…”

Section: Effects Of Jak Inhibitors On T Cellsmentioning

confidence: 98%

Immunological Consequences of JAK Inhibition: Friend or Foe?

McLornan

Khan

Harrison

2015

Curr Hematol Malig Rep

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Over the last decade, unparalleled advances have been made within the field of 'Philadelphia chromosome'-negative myeloproliferative neoplasms (MPN) regarding both disease pathogenesis and therapeutic targeting. The discovery of deregulated JAK-STAT signalling in MPN led to the rapid development of JAK inhibitor agents, targeting both mutated and wild-type JAK, which have significantly altered the therapeutic paradigm for patients with MPN. Although the largest population treated with these agents incorporates those with myelofibrosis, increasing data supports potential usage in other MPNs such as essential thromocythaemia and polycythaemia vera. Many MPNs are associated with a hyperinflammatory state and deregulation of immune homeostasis. Over the last few years, research has focused on attempting to decipher the complex and context-dependent changes that contribute to this immune deregulation. Moreover, very recent studies have demonstrated significant JAK inhibitor-mediated effects within the T cell, natural killer cell and dendritic cell compartments following exposure to JAK inhibitors. In parallel, case reports of infections occurring following exposure to ruxolitinib, many of which are atypical, have focused research efforts on delineating JAK inhibitor-associated immunological consequences. Within this review article, we will describe what is currently known about MPN-associated immune deregulation and JAK inhibitor-mediated immunomodulation.

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“…As expected, anaemia and thrombocytopenia were the most common side effects, mediated by JAK2 inhibition. In parallel, JAK1 inhibition is responsible for decrease in pro‐inflammatory cytokines resulting in decrease of disease‐related symptoms but also in impaired immune function . Indeed, several abnormalities both in adaptive and innate immunity were demonstrated after RUX exposure .…”

Section: Introductionmentioning

confidence: 99%

Epidemiology, outcome, and risk factors for infectious complications in myelofibrosis patients receiving ruxolitinib: A multicenter study on 446 patients

Polverelli

Palumbo

Binotto

et al. 2018

Hematological Oncology

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Infections represent one of the major concerns regarding the utilization of ruxolitinib (RUX) in patients with myelofibrosis. With the aim to investigate epidemiology, outcome and risk factors for infections in RUX-exposed patients, we collected clinical and laboratory data of 446 myelofibrosis patients treated with RUX between June 2011 and November 2016 in 23 European Hematology Centers. After a median RUX exposure of 23.5 months (range, 1-56), 123 patients (28%) experienced 161 infectious events (grades 3-4 32%, fatal 9%), for an incidence rate of 17 cases per 100 pts/y. The rate of infections tended to decrease over time: 14% of patients developed the first infection within 6 months, 5% between 6 and 12 months, 3.7% between 12 and 18 months, 3.4% between 18 and 24 months, and 7.9% thereafter (P < .0001). Respiratory tract infections were more frequently observed (81 events, 50%), and bacteria were the most frequent etiological agents (68.9%). However, also viral (14.9%) and fungal infections (2.5%) were observed. In multivariate analysis, previous infectious event (HR 2.54; 95% CI, 1.51-4.28; P = .0005) and high international prognostic score system category (IPSS) (HR 1.53; 95% CI, 1.07-2.20; P = .021) significantly correlated with higher infectious risk. On the contrary, spleen reduction ≥50% from baseline after 3 months of treatment (P = .02) was associated with better infection-free survival. Taken together, these findings reinforce the concept of disease severity as the most important risk factor for infections, and describe, for the first time, that a positive therapeutic effect in reducing splenomegaly may also reduce subsequent infectious complications.

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Specificity of JAK-kinase inhibition determines impact on human and murine T-cell function

Cited by 22 publications

References 14 publications

Frequency of infections in 948 MPN patients: a prospective multicenter patient-reported pilot study

Frequency of infections in 948 MPN patients: a prospective multicenter patient-reported pilot study

Immunological Consequences of JAK Inhibition: Friend or Foe?

Epidemiology, outcome, and risk factors for infectious complications in myelofibrosis patients receiving ruxolitinib: A multicenter study on 446 patients

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