PROLONGED ADMINISTRATION OF LOW-DOSE INTERLEUKIN-2 IN HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED MALIGNANCY RESULTS IN SELECTIVE EXPANSION OF INNATE IMMUNE EFFECTORS WITHOUT SIGNIFICANT CLINICAL TOXICITY

Ten adult patients with human immunodeficiency virus (HIV)-associated malignancies (five with lymphoma and five with Kaposi's Sarcoma) were treated with a daily subcutaneous injection of interleukin-2 (IL-2) fo r 90 consecutive days in a phase I dose-escalation study, Seven patien ts had absolute CD4 counts below 200/mm(3) at the time malignancy was diagnosed. Each lymphoma patient had obtained a complete or partial re mission with standard chemotherapy before initiating IL-2, The daily d ose of IL-2 did not change during the 90-day course of therapy. Sevent een courses of IL-2 therapy were completed at doses ranging from 0.4 x 10(6) U/m(2)/d to 1.2 x 10(6) U/m(2)/d without significant (grade III ) toxicity. Two of two patients experienced grade ill toxicity within 21 days of initiating IL-2 at a dose of 1.4 x 10(6) U/m(2)/d, but both patients subsequently completed 90 days of therapy at the maximum tol erated dose (MTD) of 1.2 x 10(6) U/m(2)/d. Although there were no sign ificant increases or decreases in T-cell subsets at any dose level, th ere was an increase in absolute natural killer (NK) cell number at the three highest doses of IL-2 (mean percent increase 247; 95% confidenc e interval, 124 to 369) that was statistically significant (Wilcoxon o ne-sample signed rank test, P = .015), One patient developed an anti-I L-2 antibody titer that correlated with minimal NK cell expansion in v itro and in vivo. An increase in eosinophils was noted during 9 of 17 courses of IL-2 therapy without correlation to IL-2 dose, prior course of IL-2, or NK cell expansion. At the MTD, there was no consistent in crease in the plasma HIV RNA level over time. Three of 10 patients had progressive disease while on study. During 50 months of IL-2 therapy, no patient was treated for an opportunistic infection. We conclude th at daily low dose subcutaneous IL-2 can be self-administered safely wi th good compliance for prolonged periods of time to patients with HIV- associated malignancies, including those with profound immune deficien cy. The majority of patients show selective expansion of innate immune effecters, ie, NK cells and/or eosinophils, in the absence of signifi cant clinical toxicity or increased viral burden. These results sugges t that low-dose IL-2 therapy should be studied further in phase II cli nical trials for evidence of activity against malignancy and opportuni stic infection in this patient population. (C) 1995 by The American So ciety of Hematology.