Hematotoxicity of interleukin-2 in man: clinical effects and comparison of various treatment regimens.
BACKGROUND
Immunotherapy using recombinant human interleukin-2 (rIL-2) produces objective responses in a proportion of advanced cancer patients. While early investigators employed intravenous (i.v.) treatment regimens, recent clinical trials applied therapy schedules via subcutaneous (s.c.) injection, mostly in combination with recombinant human interferon-alpha (rIFN-alpha). There were no significant differences in reported response rates between i.v. and s.c. treatment regimens.


METHODS
We retrospectively evaluated 148 treatment cycles of s.c. immunotherapy administered to 107 outpatients. Adverse effects of s.c. cytokine therapy were described with regard to hematotoxicity, and compared to adverse effects reported upon high- or intermediate-dose i.v. rIL-2 therapy. Our study population consisted of 15 patients who received s.c. rIL-2 at doses of 4.8-14.4 million IU/m2/day on 5 days per week, 20 patients who were treated with rIFN-alpha 2b at 3.0-6.0 million U/m2/day thrice weekly, and 72 patients who were given s.c. rIFN-alpha 2b at 6.0 million U/m2/day thrice weekly plus s.c. rIL-2 at 14.4-18.0 million IU/m2/day on days 1 and 2, followed by 4.8 million IU/m2/day, 5 days per week.


RESULTS
Subcutaneous immunotherapy as administered in this study was well tolerated in the outpatient setting. Thus, there were no treatment-related deaths, and no patient developed grade III or IV (WHO) toxicity. Subcutaneous rIL-2 as a single agent produced grade II anemia and granulocytopenia in 7% of patients, respectively. In combination with s.c. rIFN-alpha, s.c. rIL-2 yielded grade II anemia and granulocytopenia in 8 and 14% of patients, respectively. In comparison, rIFN-alpha as a single agent produced grade III anemia and grade I granulocytopenia in 5 and 20% of patients, respectively. Upon s.c. rIL-2/rIFN-alpha combination therapy, a mean hemoglobin nadir of 114.4 g/l (p < 0.0001 when compared to baseline) was noted, and the mean granulocyte nadir was 2.3/nl (p < 0.0005). These mild laboratory changes due to cytokine-induced hematotoxicity were in marked contrast to severe anemia, thrombocytopenia, and granulocytopenia reported upon i.v. rIL-2 therapy.


CONCLUSIONS
Palliative s.c. rIL-2-based immunotherapy as used in this study abrogates profound hematotoxicity, previously seen upon rIL-2-based i.v. immunotherapy. Subcutaneous rIL-2/rIFN-alpha combination therapy can be given in the ambulatory setting with good practicability and excellent safety. This outpatient regimen is as effective in advanced renal cell cancer as the most aggressive i.v. rIL-2-based protocols reported.
Schomburg
A
A
Department of Hematology and Oncology, MHH University Medical Center, Hannover, FRG.
Kirchner
H
H
Atzpodien
J
J
D000328:Adult; D000368:Aged; D000553:Ambulatory Care / Q000379:methods / Q000706:statistics & numerical data; D001769:Blood / Q000187:drug effects*; D016009:Chi-Square Distribution; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods / Q000706:statistics & numerical data; D007370:Interferon Type I / Q000008:administration & dosage / Q000009:adverse effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000453:epidemiology / Q000628:therapy; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012189:Retrospective Studies
D007370:Interferon Type I; D007376:Interleukin-2; D011994:Recombinant Proteins