JAK inhibitors: a home run for GVHD patients?

Teshima, Takanori

doi:10.1182/blood-2014-04-570325

Cited by 25 publications

(15 citation statements)

References 6 publications

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“…Characterisation demonstrated attenuated differentiation of CD4 + cells into IFN-γ-and IL-17A-producing cells in parallel with an increase in tolerogenic Tregs. As discussed by Teshima et al in the specific context of GVHD, ruxolitinib appeared to spare the IL2-JAK3-STAT5 axis, which may in part explain the increase in Tregs, yet it remains unclear what contribution ruxolitinib-mediated APC inhibition is making towards attenuation of GVHD [82]. This preliminary data led to the use of ruxolitinib in six patients with either grade 3 or 4 heavily treated or steroid refractory GVHD and reported rapid and clinically relevant responses.…”

Section: Application Of Jaki Immunosuppressive Properties To Other DImentioning

confidence: 78%

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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Section: Application Of Jaki Immunosuppressive Properties To Other DImentioning

confidence: 78%

Immunological Consequences of JAK Inhibition: Friend or Foe?

McLornan

Khan

Harrison

2015

Curr Hematol Malig Rep

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“…However, there are still issues to be clarified as is the role of ruxolitinib in regulatory T cells or its relationship with atypical opportunistic infections …”

Section: Introductionmentioning

confidence: 99%

Ruxolitinib treatment for steroid refractory acute and chronic graft vs host disease in children: Clinical and immunological results

et al. 2018

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Ruxolitinib is a promising treatment for steroid refractory graft-vs-host disease (GvHD). However, data concerning effects on T cells are probably involved in increased risk of opportunistic infections. We analyzed clinical and immunological changes in children with GvHD taking ruxolitinib. Twenty-two children that underwent transplantation and received ruxolitinib were included. Ruxolitinib indication was acute and chronic GvHD in 13 and 9 patients, respectively.Overall response rate (ORR) in acute GvHD and chronic GvHD was high, of 77% and 89%, respectively. Ruxolitinib was associated with an increase in CD4 effector memory (EM), and decrease of CD4 central memory percentage. CD4 regulatory T cells percentage decreased significantly. Patients who achieved complete response to ruxolitinib had higher natural killer (NK) cells before ruxolitinib that patients who did not respond. Also there was an increase of CD4 lymphocytes percentage, with decrease of CD8 and NK cells percentage in responders against non-responders. There were 54%, 18% and 13% of infections caused by virus, bacteria and fungi, respectively. Cumulative incidence of relapse and non-relapse mortality was 19 AE 9% and 28 AE 10%, respectively. Overall survival and disease-free survival rate at 2 years were 62 AE 11% and 58 AE 11%, respectively. Ruxolitinib is a promising treatment for acute and chronic GvHD with a high ORR of 77% and 89%, respectively. It produces important changes in immune system, such as increase of CD4 EM cells and decrease in NK and regulatory T cells. Now, we need pharmacokinetic studies to determine ruxolitinib dose in children and close surveillance and antimicrobial prophylaxis.

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“…The possible efficacy of JAK1/2 blockade on cGVHD may be the result of its inhibitory effect on proinflammatory cytokines including interferon‐γ, interleukin (IL)‐2, IL‐6, IL‐12 and IL‐23 . JAK1/2 selective inhibitors (in contrast to JAK3 inhibitors) may spare regulatory T cells, which are critical for preserving peripheral tolerance following AHSCT . In our cohort of heavily pretreated patients with severe sclerodermatous cGVHD of the skin, ruxolitinib led to a partial improvement in skin softness in the majority of cases (eight of 12 patients), but the total surface area affected by sclerosis remained the same.…”

mentioning

confidence: 95%

“…Corticosteroids are the mainstay treatment of cGVHD but no standard salvage therapy has been well defined for steroid refractory cGVHD . The possible efficacy of JAK1/2 blockade on cGVHD may be the result of its inhibitory effect on proinflammatory cytokines including interferon‐γ, interleukin (IL)‐2, IL‐6, IL‐12 and IL‐23 . JAK1/2 selective inhibitors (in contrast to JAK3 inhibitors) may spare regulatory T cells, which are critical for preserving peripheral tolerance following AHSCT .…”

mentioning

confidence: 99%