Proinflammatory cytokines mediate the systemic inflammatory response associated with high-dose cytarabine treatment in children

Background. Treatment with high-dose cytarabine (1-beta -D-arabinofuranosyl cytosine) is often associated with an acute febrile reaction sometimes Incl uding abdominal pain, myalgia, and rash. The similarity of these symptoms t o those caused by hypersecretion of cytokines in the systemic inflammatory response syndrome (SIRS) prompted us to investigate the plasma levels of pr oinflammatory cytokines during treatment of children with high-dose cytarab ine. Procedure. Sixteen children treated for hematological malignancies and In clinical remission were studied during treatment with six infusions of cytarabine given every 12 hr at a dose of 2g/m(2). Blood samples for analys is of tumor necrosis factor-alpha (TNF-alpha), Interferon-gamma (IFN-gamma) , interleukin-1 gamma (IL-1 gamma), interleukin-6 (IL-6), interleukin-8 (IL -8), interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-1ra) were obtained prior to treatment and subsequently at 12, 36 and 60 hr. Addi tional samples were collected as soon as fever occurred. Results. Thirteen of 16 patients developed fever at a median time of 30 hr following start of treatment. At 12 hr levels of TNF-alpha were elevated followed by a rise i n IL-6, IFN-alpha, and IL-1ra, peaking at the onset of fever. Thereafter th ese levels slowly declined whereas low IL-10 levels became detectable. Conc lusions. We conclude that high-dose cytarabine treatment often induces rele ase of TNF-alpha followed by the sequential release of other proinflammator y cytokines. Most likely these cytokines mediate the development of symptom s comprising the cytarabine syndrome. (C) 2001 Wiley-Liss, Inc.