Interferon-alpha-induced biologic modifications in patients with chronic myelogenous leukemia.

Serum neopterin (Np), beta 2-microglobulin (beta 2-M), and 2',5'-adenylate (2',5'A) levels and intracellular 2',5'A and human Mx (Hu-Mx) protein synthesis were measured in 20-24 chronic myeloid leukemia patients before and during 1 year of IFN-alpha treatment and in a further 8-9 patients before and at the end of the first and second treatment weeks only. Univariate analysis showed that IFN-alpha increased Np and 2',5'A serum levels and intracellular concentrations of 2',5'A and Hu-Mx significantly from the end of the first week to month 12 of therapy. The biologic marker profiles were similar in cytogenetic responders and nonresponders, as well as in patients treated with IFN-alpha early (< 12 months from diagnosis) or late (after > 12 months standard chemotherapy). Further, there were no differences in the short-term (first 14 days) or long-term (during 12 month therapy) induction of the biologic markers irrespective of whether IFN-alpha 2a or IFN-alpha 2b was given. Because multivariate analysis revealed no significant interactions between cytogenetic response, time to treatment, and type of IFN-alpha used, increments in intracellular 2',5'A and Hu-Mx protein were similar at all study times for all factor combinations tested. Np levels varied significantly only during the first 14 therapy days; changes in serum 2',5'A were never statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural-killer-stimulatory effect of combined low-dose interleukin-2 and interferon beta in hairy-cell leukemia patients.

The association of low doses of interleukin-2 (IL-2; 5 IU/ml) and interferon beta (IFN beta; 10 IU/ml) induced an additive or synergic stimulatory effect on natural killer (NK) activity (32%) in peripheral blood samples from hairy-cell leukemia patients, both those with active disease and those in remission. The synergic NK stimulatory effect was more commonly found in samples from patients with active disease, while the additive effect was more frequent in the patients in remission. The IL-2/IFN beta combination provoked a nonadditive nonsynergic NK-stimulatory effect in a further 19.8% samples. The targets of the IL-2/IFN beta combination were typical NK cells, as shown by the fact that there was increased cytotoxicity (synergic, additive or nonadditive nonsynergic) against the K562, but not the Daudi cell line in peripheral blood mononuclear cell samples treated with the combination of the two cytokines. When CD16+/CD56+ or CD57+/CD16+/CD56+ cells were removed, the NK-stimulatory effect was lost. The fact that the NK-cell-enhancing activity of the IL-2/IFN beta combination was reduced when Percoll fractions 2 and 3 were used, but still persisted in 66% of tests, may have been due to cytotoxicity being higher in the untreated fractions 2 and 3 than in the untreated unfractionated samples. One of the factors responsible for the NK-stimulatory effect appears to be the capacity of the IL-2/IFN beta combination to trigger an increase in IFN gamma synthesis. If similar experiments give like results in samples from patients suffering from other B-cell lymphoproliferative, or HIV-associated disorders, all of which are characterized by a deficiency in NK activity, it should be possible to use low-dose IL-2/IFN beta to treat these disorders and, perhaps, residual neoplastic disease without exposing the patient to undue toxicity. Further, by testing other combinations one should be able to identify the lowest IL-2 and IFN beta doses that would effectively boost the additive or synergic effect in a greater number of cases.

Double-blind randomized phase I study on the clinical tolerance and pharmacodynamics of natural and recombinant interferon-beta given intravenously.

The clinical tolerance and biological properties of 6 x 10(6) IU of Chinese hamster glycosylated recombinant interferon-beta (rHuIFN-beta) and natural IFN-beta (Frone) given i.v. were compared in 12 healthy volunteers in a randomized cross-over, double-blind trial. All subjects received a single injection of each type of IFN-beta. Both were well tolerated and provoked similar changes in clinical indices. Serum neopterin (Np) values increased significantly from the 24th to 72nd h post-injection of rHuIFN-beta and Frone. beta 2-Microglobulin (beta 2-M) serum levels were statistically above baseline 24-96 h after rHuIFN-beta, and from the 24th to the 120th h with Frone. Both IFNs provoked a rise in intracellular 2',5'-adenylate (2-5A) levels from the 10th to the 48th h, as well as in Hu-Mx synthesis, which was significant from the 10th to the 96th h. Serum levels of 2-5A, interleukin-1 alpha (IL-1 alpha), and interleukin-1 beta (IL-1 beta) remained unchanged. There were no statistical differences in the changes provoked by the two differently derived IFN-beta in any of the biological parameters studied. Overall, the results of this study indicate that rHuIFN-beta and Frone have similar pharmacodynamics.

IFN-beta induced biochemical and immunological modifications in hairy cell leukemia patients.

BACKGROUND: Although IFN-beta is 30-40% homologous with IFN-alpha, its intrinsic biological properties are not identical. Compared with IFN-alpha, IFN-beta exerts greater in vitro antiproliferative activity on many cell lines, stimulates peripheral blood stem cells of hairy-cell leukemia (HCL) patients to differentiate to erythroid burst forming cells, has higher specific type I IFN receptor affinity and modulates the expression of class II histocompatibility antigens. IFN-beta would, therefore, be expected to have a greater, or at least similar, antitumor activity as that of the various types of IFN-alpha. METHODS: We have treated 12 patients affected by HCL with IFN-beta and have investigated the biological and immunological changes induced by such treatment. RESULTS: A rise in beta 2-microglobulin and neopterin values throughout IFN-beta therapy was documented in most patients. An increase in NK activity was observed only in clinical responders whose CD57+/CD16+ cell ratio dropped below baseline. There was also a modulation in IFN-gamma synthesis that was dependent on baseline levels and in line with the clinical response. IFN-beta provoked a reduction in CD3+ and CD4+ cell subsets in patients with WBC greater than or equal to 10.0 x 10(9)/1 and greater than or equal to 50% circulating HCs, an expansion in absolute number of CD3+ and CD8+ cell fractions and a slight rise in the absolute values of CD2+ and CD4+ cell subpopulations in patients with WBC less than or equal to 5.0 x 10(9)/1 and less than or equal to 50% circulating HCs. There was no correlation between either the IFN-beta induced increase in beta 2-M or Np levels and clinical response. Most immunological parameters improved or normalized later during the course of IFN-beta treatment, when pathological-hematological signs of disease remission were already evident. CONCLUSIONS: The relevance of the IFN-beta induced changes as well as that of the IFN-alpha induced biological effects in the clinical control of HCL remain unclear.

GM-CSF: clinical trials in non-Hodgkin's lymphoma patients with chemotherapy induced leucopenia.

Fourteen patients (M/F, 6/8; age, 48/23-64 yrs) with relapsing or primary resistant intermediate-high grade non-Hodgkin lymphomas were treated with ARA-C (2 g/m2 x 4 on days 1 and 2), DDP (100 mg/m2 96 hr infusion) and VP-16 (150 mg/m2 on days 1, 2 and 3). GM-CSF or placebo was administered from the 5th day until neutrophil count reached greater than or equal to 1000/microliters on 2 consecutive days. Three PR and 6 CR were documented. Two CR pts are still in CR at 19 and 23.5 months. With the exception of one case of cerebral haemorrhage, life-threatening liver toxicity, exfoliative colitis, capillary leak syndrome and anaphylactoid reaction, the protocol regimen provoked only modest haematological and extra-haematological toxicities.

Biochemical and immunological responses of hairy cell leukemia patients to interferon beta.

Ten hairy-cell leukemia patients were treated with interferon beta (IFN-beta) at a dose rate of 2 x 10(6) IU/m2 x 5 days for 4 weeks (induction therapy) and, thereafter, at the same dose three times a week for 11 months (maintenance therapy). The effect of this treatment on serum neopterin, beta 2-microglobulin, (2'-5')oligoadenylate [(2'-5')An] levels, intracellular (2'-5')An values and human Mx protein synthesis was analysed. There were significant rises in serum neopterin and (2'-5')An levels during both induction and maintenance, whereas beta 2-microglobulin levels rose only during induction. Rises in intracellular (2'-5')An were documented mainly during induction, but they were not significantly higher than pretherapy values. IFN beta provoked an increase in human Mx protein synthesis over the entire induction-maintenance period, but was only significantly higher than baseline during induction. All markers proved useful for monitoring the effects of IFN beta dose schedules, but were not predictive of clinical outcome. Natural killer activity and IFN gamma production, which were initially defective, followed a different trend from that of the other factors studied, in that increases were documented only late in the course of therapy when the disease was already in remission.

Phase I-II trial on natural beta interferon in chemoresistant and relapsing multiple myeloma.

One Waldenström's disease and 16 multiple myeloma patients were administered IFN-beta I.V. at the dose of 6 x 10(6) IU/m2 over 6 hours for 7 days on alternate weeks for a total of 3 cycles, and then continued at the same dose, twice a week, for an additional 24 weeks. Four patients had initially proved to be, and 6 became, resistant to chemotherapy. Disease progressed after chemotherapy was discontinued in another 7 patients: 3 SD and 4 PR. One of the 16 evaluable patients achieved an MR, and 11 experienced brief stabilization of disease (median 14 weeks, range 6-34). In addition, cellular response to IFN-beta was documented by increased B2-microglobulin and neopterin levels, even as early as 24 hours after the 1st IFN injection of the 1st and 2nd cycles. Hemtological and extrahematological toxicity was low despite the fact that 8/16 patients had severely or moderately reduced bone marrow reserve at the beginning of treatment. Since vincristine-adriamycin-dexamethasone and etoposide-dexamethasone-cytarabine-cisplatin combinations achieve high response rates in resistant and relapsing multiple myeloma patients, IFNs alone should be reserved as third-line therapy for those subjects who are resistant to, or not candidates for, these chemotherapeutic regimens. The low toxicity and the modulation of B2-microglobulin and neopterin should encourage studies aimed at defining the optimal antitumor dose of IFN-beta that could be used in combination with conventional chemotherapeutic regimens to improve the response rate in multiple myeloma patients.

Response to intermediate and standard doses of IFN-beta in hairy-cell leukaemia.

Thirteen hairy-cell leukaemia patients were treated with IFN-beta (6 X 10(6) IU/m2) for 7 days, alternate weeks, for three cycles. IFN-beta was then continued at the same dose twice a week for 24 weeks. Treatment was discontinued in 2 non-responders and 2 partial responders (1 haem PR, 1 path PR) because of complications unrelated to IFN. The objective response in the nine patients who completed therapy was 66% (1 CR, 3 path PR and 2 haem PR); 2 patients achieved MR. Responses lasted from 5 to 45+ months. Four newly diagnosed patients and 3 in relapse after discontinuation of IFN-beta therapy (6 X 10(6) IU/m2), were treated with a lower dose of IFN-beta (2 X 10(6) IU/m2). The objective response to this dose was 57% (3 path PR, 1 haem PR). Another patient obtained MR. No patient has relapsed 6-12 months after therapy discontinuation. IFN-beta was well tolerated, especially at the lower dose and no chronic toxicity was observed. Therefore IFN-beta may be suggested as an alternative treatment for HCL.