The Effect of Tumor Necrosis Factor (TNFα) Inhibition on Platelet Counts in Adults and Children with Persistent ITP.

Abstract

Immune Thrombocytopenic Purpura (ITP) is hematologic disorder caused by autoimmune opsonization and premature destruction of platelets. Approximately 20% of children and the majority of adults will have a chronic course of ITP with antibody-mediated destruction of platelets and the inability to clear immune complexes. Pro-inflammatory cytokines IL-2, TNF-α and IFN-γ are secreted following a Th1 response and are elevated in patients with chronic ITP. Recent treatments for chronic ITP in adults and children have focused on quelling dysregulated T and B lymphocyte activity. We conducted a pilot clinical trial of etanercept, a fusion peptibody composed of the soluble TNF-α receptor and the Fc portion of Ig. Hematologic and immunologic responses were measured before, during (blood counts only) and after a 12-week regimen of 0.4mg/kg/dose (max dose 25 mg) of subcutaneous etanercept, given twice weekly. Only fixed-dose prednisone or danazol were allowed as concomitant ITP medications. Cytokine concentrations were measured pre- and post-treatment from plasma and cultured lymphocytes (unstimulated or PHA- [2.5ng/ml] stimulated). Sixteen patients (9 male, 7 female), with chronic ITP (8 post-splenectomy) an initial platelet concentration < 30 × 109/L were enrolled with data evaluable for 15. The mean age of the patients was 31 years (median 32, min/max 7/52 years). One patient withdrew due to dizziness thought related to the study drug. One patient developed autoimmune hemolytic anemia, was diagnosed with Evans syndrome at treatment week 3 and withdrew from the study. Otherwise, no severe or serious related adverse events were observed. Two patients had a complete platelet response (CR, plt count > 150 × 109/L at least 6 weeks post treatment), 6 had a partial response (PR, plt count > 30 × 109/L and double baseline plt count), one had a minimal response (MR, plt count > 30 × 109/L) and 5 had no platelet response (NR). Two of the patients with PR had a platelet count rise that lasted at least until the end of the 8 week post-treatment observation period. The platelet response rate in nonsplenectomized and splenectomized patients was 67% and 28%, respectively, p = 0.1. Concentrations of IL-1β, IL-4, IL-6, IL-10 IFN-γ and TGF-β, before and at the end of the 12-week treatment course, showed marked inter-patient variation and did not predict the platelet count outcome. Both patients that had a CR had a reduction in PHA-stimulated TNF-α of 33 and 30%, respectively. Others with NR to treatment had similar declines in TNF-α, however. Although the precise mechanism of action is unclear, etanercept treatment led to at least a partial platelet response in 50% of patients with persistent ITP and was well-tolerated.