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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
ZP Bernstein, MM Porter, M Gould, B Lipman, EM Bluman, CC Stewart, RG Hewitt, G Fyfe, B Poiesz and MA Caligiuri
Department of Hematologic Oncology, Roswell Park Cancer Institute, Buffalo,
NY 14263, USA.
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) for 90
consecutive days in a phase I dose-escalation study. Seven patients had
absolute CD4 counts below 200/mm3 at the time malignancy was diagnosed.
Each lymphoma patient had obtained a complete or partial remission with
standard chemotherapy before initiating IL-2. The daily dose of IL-2 did
not change during the 90-day course of therapy. Seventeen courses of IL-2
therapy were completed at doses ranging from 0.4 x 10(6) U/m2/d to 1.2 x
10(6) U/m2/d without significant (grade III) toxicity. Two of two patients
experienced grade III toxicity within 21 days of initiating IL-2 at a dose
of 1.4 x 10(6) U/m2/d, but both patients subsequently completed 90 days of
therapy at the maximum tolerated dose (MTD) of 1.2 x 10(6) U/m2/d. Although
there were no significant increases or decreases in T-cell subsets at any
dose level, there was an increase in absolute natural killer (NK) cell
number at the three highest doses of IL-2 (mean percent increase 247; 95%
confidence interval, 124 to 369) that was statistically significant
(Wilcoxon one-sample signed rank test, P = .015). One patient developed an
anti-IL-2 antibody titer that correlated with minimal NK cell expansion in
vitro 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 increase 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 that daily low dose
subcutaneous IL-2 can be self-administered safely with good compliance for
prolonged periods of time to patients with HIV-associated malignancies,
including those with profound immune deficiency. The majority of patients
show selective expansion of innate immune effectors, ie, NK cells and/or
eosinophils, in the absence of significant clinical toxicity or increased
viral burden. These results suggest that low-dose IL-2 therapy should be
studied further in phase II clinical trials for evidence of activity
against malignancy and opportunistic infection in this patient population.
Volume 86,
Issue 9,
pp. 3287-3294,
11/01/1995
Copyright © 1995 by The American Society of Hematology
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