Disseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report

Abstract

BackgroundPrimary myelofibrosis is a myeloproliferative disorder characterized by bone marrow fibrosis, abnormal cytokine expression, splenomegaly and anemia. The activation of JAK2 and the increased levels of circulating proinflammatory cytokines seem to play an important role in the pathogenesis of myelofibrosis. Novel therapeutic agents targeting JAKs have been developed for the treatment of myeloproliferative disorders. Ruxolitinib (INCB018424) is the most recent among them.Case presentationTo our knowledge, there is no evidence from clinical trials of an increased risk of tuberculosis during treatment with JAK inhibitors. Here we describe the first case of tuberculosis in a patient treated with Ruxolitinib, a male with a 12-year history of chronic idiopathic myelofibrosis admitted to our Institute because of fever, night sweats, weight loss and an enlarging mass in the left inguinal area for two months.ConclusionTreatment with Ruxolitinib may have triggered the reactivation of latent tuberculosis because of an inhibition of Th1 response. Our case highlights the importance of an accurate screening for latent tuberculosis before starting an anti-JAK 2 treatment.

JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms

“…The observation that the therapeutic effects are irrespective of the patients' JAK mutational status and that the compound induces only limited anticlonal activity (6) suggests that it profoundly modifies the inflammatory microenvironment. The idea that JAK inhibitors are immunosuppressive is underscored by an increased infection rate of patients treated with ruxolitinib (7)(8)(9)(10)(11), but also by its potential benefit in inflammatory-driven cancers, such as pancreatic cancer with increased C-reactive protein levels (12). In line with these clinical observations, we recently provided evidence that JAK inhibitors markedly impair dendritic cell biology (13).…”

“…Accordingly, NK cells are highly efficient in the recognition and killing of virally infected cells (47), and, as a consequence, NK cell deficiency leads to a high susceptibility to various infections (48). Intriguingly, ruxolitinib therapy is also associated with severe infections, among which disseminated tuberculosis (7,8), reactivation of hepatitis B (9), progressive multifocal leukencephalopathy (10), toxoplasmosis retinitis (11), and Epstein-Barr virus-associated aggressive lymphoma (J. Richter, Lund University, Lund, Sweden; personal communication, June 2014) are the most alarming ones. Moreover, reactivation of herpes simplex and varicella zoster infections in ruxolitinib-treated patients is frequent, similar to patients with an inherited functional NK cell deficiency (49).…”

Pneumocystis jirovecipneumonitis complicating ruxolitinib therapy

“…There have been recent isolated reports of toxoplasma retinitis,4 cryptococcal pneumonia,5 disseminated tuberculosis,6 progressive multifocal leukoencephalopathy7 and sino-orbital mucormycosis8 in patients receiving ruxolitinib. Treatment with ruxolitinib has also been associated with the reactivation of latent infections with hepatitis B virus9 and herpes simplex virus 10.…”

Efficacy of ruxolitinib for myelofibrosis

“…Recently, there were several cases reports of systemic, opportunistic infections in patients being treated with ruxolitinib, including hepatitis B virus reactivation 40 , herpes simplex reactivation 41 , Cryptococcus neoformans pneumonia 42 , toxoplasmosis retinitis 43 , tuberculosis 44 and progressive multifocal leukoencephalopathy (the latter being only a single case) 45 . There is some in vitro evidence to suggest that ruxolitinib impairs dendritic cell functions, which may result in impaired CD4+ and CD8+ T-lymphocyte activation 46 .…”