title: Tumor necrosis factor alpha modifies resistance to interferon alpha in vivo: first clinical data.
abstract: Patients with Philadelphia-positive chronic-phase chronic myelogenous leukemia (CML) resistant to interferon (IFN) alpha were treated in a phase I/II study with recombinant human tumor necrosis factor alpha to overcome IFN alpha resistance. Doses of 40, 80, 120 or 160 micrograms/m2 TNF alpha were given as 2-h infusions on 5 consecutive days every 3 weeks. IFN alpha (4 x 10(6) 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 TNF alpha 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 micrograms/m2 and 160 micrograms/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 TNF alpha treatment. These preliminary data point to significant clinical efficacy of additionally applied TNF alpha in IFN alpha-resistant CML patients.
authors.affiliation: Innere Klinik und Poliklinik (Tumorforschung), University of Essen, Federal Republic of Germany.
authors.forename: T
authors.initials: T
authors.lastname: Moritz
authors.forename: O
authors.initials: O
authors.lastname: Kloke
authors.forename: M
authors.initials: M
authors.lastname: Nagel-Hiemke
authors.forename: G
authors.initials: G
authors.lastname: Kummer
authors.forename: U B
authors.initials: UB
authors.lastname: Wandl
authors.forename: B
authors.initials: B
authors.lastname: Opalka
authors.forename: B
authors.initials: B
authors.lastname: Plappert
authors.forename: J
authors.initials: J
authors.lastname: Kempeni
authors.forename: S
authors.initials: S
authors.lastname: Seeber
authors.forename: N
authors.initials: N
authors.lastname: Niederle
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000032:analysis; D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000187:drug effects; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D017471:Receptors, Interferon / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D016898:Interferon-alpha; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015088:2',5'-Oligoadenylate Synthetase