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.

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.

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.

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.

Biochemical host response to interferon-beta.

To assess influence of host response to interferon-beta (IFN-beta), on biochemical parameters, beta 2-microglobulin (beta 2-M) and neopterin were evaluated in 15 and 12 patients respectively before and 24 h after 1-46 X 10(6) IU intravenously (i.v.) IFN-beta given every other day. In 4 additional patients, both molecules were determined before and after 24, 48, 72, and 96 h of weekly IFN-beta injections. Serum beta2-M levels significantly increased 24 h after IFN-beta administration in the overall group of 15 patients treated with the alternate day schedule (p = 0.003) as well as in the group of patients treated with the weekly schedule (p = 0.00003). Maximum induction of beta 2-M was observed 24 h after a single weekly IFN-beta injection, but the levels of this protein 72 h after still remained significantly higher than baseline values (p = 0.001). This demonstrates the progressive accumulation of beta 2-M in the circulation produced by the continuous IFN administration. Nevertheless, in patients treated with both IFN treatment schedules, a clear correlation between the increments of beta 2-M and the IFN-beta doses was observed (p = 0.00002 and p = 0.0016 for the alternate day and the weekly schedule respectively). Furthermore the under curve area (AUC) of 48 h beta 2-M levels after IFN administration significantly rose (p less than 0.05) with increasing IFN doses in 4/6 patients. In spite of the accumulation of beta 2-M in the circulation, the overall serum values of this protein 24 h after each successive IFN-injection, in the 15 patients receiving the alternate-day treatment, were significantly higher than before the immediate preceding dose both in patients with initially normal and those with initially high base levels (p = 0.00055 and p = 0.011, respectively). As with beta 2-M, neopterin levels significantly rose during IFN treatment (p less than 0.05) in the group of patients as a whole. After single weekly IFN-beta injections, maximum induction of neopterin was observed 24 h after administration, then the levels of this molecule slowly declined towards the baseline levels, but 96 h after, its levels were still significantly elevated (p less than 0.00001). Neopterin induction was not related to IFN-beta doses, but the levels of this molecule both before and after IFN administration were correlated with an increase in the number of IFN injections (p = 0.0006 and p = 0.0009, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)