Interferon-alpha and interleukin-2 in the treatment of metastatic melanoma. Comparison of two phase II trials.

BACKGROUND: Interferon-alpha (IFN alpha) and interleukin-2 (IL-2) are active agents against malignant melanoma. There is, however, no consensus on the optimal dosing schedule of both drugs. This is a report of two sequential immunotherapy trials in patients with metastatic melanoma using two different IL-2 dosing schedules. METHODS: Schedule A consists of IFN alpha, 10 million U/m2/day subcutaneously for 5 days, followed by continuous intravenous infusion of IL-2, 1 mg/m2/24 hours for 5 days. Schedule B consists of the same dose of IFN alpha, but a modified regimen of IL-2. To improve the induction of high-affinity IL-2 receptors, the initial IL-2 dose was increased (1 mg/m2/6 hours, followed by 1 mg/m2/12 hours, and 1 mg/m2/24 hours). To reduce toxicity, the dose was reduced thereafter to 0.25 mg/m2/24 hours for the following 3 days. Both regimens were repeated after 4 weeks. RESULTS: 27 patients were treated with schedule A with a response rate of 18% (1 complete response [CR], 4 partial responses [PR]), 95% confidence interval, 6-36%. The response rate in 27 patients treated with schedule B was 41% (3 CR, 8 PR), 95% confidence interval, 22-61%. Severe, often dose-limiting toxicity was associated with IL-2 in schedule A, particularly hypotension and fluid retention. Toxicity was reduced significantly in schedule B. Maximal serum levels of soluble CD25 were 17,022 +/- 13,070 U/ml in schedule A, and 31,148 +/- 4227 U/ml in schedule B (P < or = 0.01). Serum levels of TNF alpha were significantly lower in schedule B than in schedule A, as were the side effects. CONCLUSIONS: Toxicity of IL-2 is reduced by modifying the schedule of administration, which also enhances the immunologic response and appears to increase the response rate.

Mitozantrone-induced toxicity and DNA strand breaks in leukaemic cells.

By applying the fluorometric analysis of DNA unwinding (FADU) the in vitro effect of mitozantrone on DNA strand breaks was studied in seven different human leukaemic/lymphoma cell lines and in fresh leukaemic samples from seven patients with acute myeloid leukaemia refractory to conventional treatment. Pulse exposure to mitozantrone for 30 min invariably caused strand breaks. In the cell lines JM 1, KM3 and RPM I 8420 DNA strand breakage was progressive upon further incubation in drug free medium. These cell lines were killed by pulse exposure to mitozantrone. In the cell lines Molt 4, Daudi, Raji and HL-60, the DNA strand breaks induced by mitozantone were only moderate and these cell lines were also resistant to killing by mitozantrone in vitro. The leukaemic cells of one of the seven patients behaved also like the cell lines that were sensitive and a complete remission was achieved in this patient using mitozantrone as single agent therapy. The other patients with a pattern similar to the resistant cell lines proved to be clinically refractory. Thus mitozantrone induces rapidly progressive DNA strand breaks as early as 30 min in leukaemic cells that are sensitive. The measurement of DNA strand breaks by the fluorometric analysis of DNA unwinding is a rapid method which might predict response to drugs whose major effect is on the induction of strand breaks.

Mitoxantrone in the treatment of relapsed and refractory acute leukemia.

Twenty-four patients with acute leukemia and blast crisis of chronic myelocytic leukemia in relapse or refractory to standard chemotherapy were eligible for treatment with mitoxantrone. Mitoxantrone was administered in a dose of 8-13 mg/m2 on five consecutive days. 5 of 20 evaluable patients were induced into complete remission, 1 patient achieved a partial remission. Side effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.

Mitoxantrone in the treatment of relapsed and refractory acute leukemia.

Twenty-four patients with acute leukemia or blast crisis (BC) of chronic myelocytic leukemia (CML) in relapse or refractory to standard chemotherapy, were eligible for treatment with mitoxantrone. Mitoxantrone (Novantrone; dihydroxyanthracenedione) was administered in a dose of 8-13 mg/m2 on five consecutive days. Five of 20 evaluable patients were induced into complete remission, one patient achieved a partial remission. Side-effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.