Mitoguazone Appears Promising in HIV-Associated Refractory NHL

ASCO LOS ANGELES--In a multicenter phase II study of mitogua-zone(MGBG) in relapsed or refractory AIDS-related non-Hodgkin's lymphoma(NHL), more than one quarter of patients responded to the drug,and all of the complete responders experienced an increase intheir CD4 counts, Alexandra M. Levine, MD, reported at ASCO.

MGBG has previously shown efficacy in non-AIDS lymphoma, is relativelynonmyelosuppressive, and crosses the blood-brain barrier, a plusin AIDS lymphoma patients who often have CNS disease, said Dr.Levine, of the University of Southern California.

Eligible patients had to have failed at least one potentiallycurative lymphoma regimen; half had failed two to five prior regimens,and 35% had primary refractory disease. The median CD4 count priorto MGBG was 73, and 92% of patients at entry had counts less than200. Ninety percent had high-grade lymphoma.

The agent was given at a dosage of 600 mg/m² IV over 30 minuteson days 1 and 8, then every 2 weeks. Patients received a medianof three doses, and about 25% received more than seven doses.

Of 27 evaluable patients, three had a complete response and foura partial response, for a total response rate of 26%. Three patientshad stable disease, and 17 progressed. The median duration ofresponse was 4 months for the complete responders and 2.5 monthsfor the partial responders. "One patient each is out 17+months in maintained complete or partial response," Dr. Levinesaid.

Response was associated with improved quality of life (eg, weightgain, improved performance status). Of special interest, all threeof the complete responders had an increase in CD4 counts, as didone of the partial responders.

Median survival from time of treatment with mitoguazone is 11months among responders, 6.6 months for those with stable disease,and 2.3 months for those with progressive disease. Toxicity wasmild, consisting primarily of a syndrome (facial flushing andcircumoral paresthesias) that occurs during infusion.

Although there was some myelosuppression in these multiply treatedpatients, it was mostly mild (grade 1 and 2); 26% had leukopenia,23% had thrombocytopenia, 17% had neutropenia, and 11% had anemia.Many of these patients were also on concurrent myelosuppressivemedication for treatment or prophylaxis of various opportunisticinfections, she pointed out.

Dr. Levine said that the data are being presented to the FDA asthe first pivotal trial. "A second pivotal trial is ongoing,with these responses already confirmed." She said that hergroup is currently testing MGBG plus radiotherapy in primary HIV-associatedCNS lymphoma.

An Old Drug Made New

Mitoguazone (MGBG) is one of the earliest drugs synthesized asan anticancer agent, with an IND number of 927, Dr. Levine saidat ASCO.

The drug works by inhibiting polyamine biosynthesis. Polyaminesare necessary for stimulation of DNA, RNA, and protein synthesis.They also stabilize membrane and cytoskeletal structures.

In the early 1960s, MGBG, given as a daily infusion for 30 days,had significant toxicity, primarily mucositis. Later, the agentwas found to have a long half-life, more than 5 days, "whichexplained the tremendous toxicity seen with a daily 30-day schedule,"she said. New schedules were then devised that have allowed currenttesting.