Tumor necrosis factor α modifies resistance to interferon α in vivo: First clinical data

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Abstract
Patients with Philadelphia-positive chronic-phase chronic myelogenous leukemia (CML) resistant to interferon (IFN) α were treated in a phase I/II study with recombinant human tumor necrosis factor α to overcome IFNα resistance. Doses of 40, 80, 120 or 160 µg/m2 TNFα were given as 2-h infusions on 5 consecutive days every 3 weeks. IFNα (4 × 106 IU/m2 s.c., daily) treatment was continued. Six patients were treated, completing 1–24 (median, 12) treatment cycles. Five of the six patients achieved partial hematological remission, while the remaining patient had to stop treatment because of WHO grade 4 thrombocytopenia following the first TNFα cycle. No complete hematologic remission or cytogenetic improvement was seen. Side-effects were similar to those described for both substances alone. Maximum tolerable TNF doses usually varied between 80 µg/m2 and 160 µg/m2. To examine possible pathways of TNF activity in these patients, interferon receptor status and (2′–5′)-oligoadenylate synthetase levels were examined in peripheral blood mononuclear cells. Both parameters remained unchanged during TNFα treatment. These preliminary data point to significant clinical efficacy of additionally applyed TNFα in IFNα-resistant CML patients.