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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.

The neurotoxicity of interferon-beta (IFN-beta) was assessed by performing electrophysiological examinations and neuropsychological tests on 22 patients with malignant hematological diseases before, during, and after IFN-beta treatment. IFN-beta (6 x 10(6) IU/m2) was infused i.v. for 6 h daily for 7 days on alternate weeks for a total of three cycles (induction therapy) and was then continued at the same dose, twice a week, for an additional 24 weeks (maintenance therapy). Twenty-one of the 22 patients were evaluable. There were no significant changes in EEGs, visual evoked potentials, sensory conduction central time or motor nerve conduction velocity of two long nerves in the 15-19 patients studied before and after induction therapy, nor in the 6-8 patients investigated at the end of maintenance therapy. Neuropsychological monitoring failed to disclose any IFN-induced deterioration in 21 patients tested before and at the end of induction therapy or in the 10 patients who were also studied at the end of maintenance therapy. Despite certain limitations in the patient follow-up, the results underline the good general tolerance of IFN-beta.

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.

A total of 19 Hodgkin's disease (HD) patients (12 male, 7 female) aged 26-67 years, who had been in complete unmaintained remission for 6 months or more when the study was initiated, were randomly given 50 mg thymostimulin (TS) i.m. daily (G1) or every other day (G2) for 35 days. A third group (G3) was not treated. Then TS, at the same dose was administered twice a week for the following 22 weeks in patients both initially receiving loading or intermittent TS treatment. When compared with age- and sex-matched controls, as a group, the patients' circulating OKT3+, OKT4+, OKT11+ and E-AETR+ cells were depressed (P less than 0.001 for both proportions and absolute numbers), whereas their OKT8+ cell population was not. Following 5 weeks of daily TS administration, the proportions and numbers of all T cell fractions significantly increased in G1 patients (P less than 0.03 for all the comparisons tested), while following intermittent TS treatment (G2) only the proportions of OKT3+ and OKT11+ cells (P less than 0.03), but not of other T cell fractions, significantly increased. In addition, no significant changes in the absolute numbers of T cell fractions were observed in this group of patients. Furthermore, no spontaneous variations in the T cell pool size occurred in untreated patients. TS maintenance therapy did not produce any further improvement in the size of overall T cells and T cell subsets but sustained percentage and absolute numbers of these cells during administration and the absolute number of T cells even after discontinuation of therapy. The TS-induced improvement in the T cell pool was not associated with any change in the size of circulating non-T lymphocytes and monocytes. In vitro phytohemagglutinin-induced interleukin-2 (IL-2) and gamma-interferon (IFN-gamma) synthesis was assessed in 11 patients (3 G1, 4 G2, and 4 G3). Although it was not statistically significant, a rise in IL-2 and IFN-gamma production was observed in TS-treated patients, but not in untreated controls. TS failed to exert any effect on the serum circulating levels of neopterin, type I and II IFN, beta-2 microglobulin (B2-M) and immunoglobulins (Ig). TS can thus improve defective T cell frequences and numbers and may modulate IL-2 and IFN-gamma production.

Plastic-adherent depleted or not depleted peripheral mononuclear blood cells (PMBC) from healthy donors showed enhanced lytic activity against 51Cr-labelled K562 target cells when exposed to thymostimulin (TS), 1 microgram ml-1, for 3 h, washed and incubated in TS-free medium before testing for natural killer (NK) cytotoxicity. No modification of NK cell activity was seen when effector cells were treated with placebo (splenic extract). The NK boosting activity of TS was lost when effector cells were treated for 3 h immediately before the performance of the cytotoxic test or when this thymic extract was added directly to the mixture of effector and target cells during the lytic phase of 51Cr release assay.