A phase I trial of interleukin 3 (IL-3) pre-bone marrow harvest with granulocyte-macrophage colony-stimulating factor (GM-CSF) post-stem cell infusion in patients with solid tumors receiving high-dose combination chemotherapy.
In humans, interleukin 3 (IL-3) administration increases the cellularity and cycling of bone marrow progenitor cell populations. Initially, in primates and then in humans, IL-3 in sequence with GM-CSF has been shown to stimulate multilineage hematopoiesis. Based upon these effects, we designed a phase I trial of daily IL-3 administered subcutaneously for 10 days at dose levels of 2.5, 5.0, 10.0, 12.5, and 15.0 micrograms/kg followed within 72 h by bone marrow harvest, high-dose chemotherapy, and following chemotherapy, a fixed dose (5.0 micrograms/kg/day) of GM-CSF and bone marrow rescue. The study was designed to assess the toxicity and biological effects of IL-3 administered alone prior to bone marrow harvest and to determine the safety and clinical effects of IL-3 stimulated bone marrow with GM-CSF following high-dose combination chemotherapy. A total of 19 patients with chemotherapy-sensitive non-hematologic malignancies (13 breast, five ovarian, and one testicular cancer) were enrolled. IL-3 up to 15.0 micrograms/kg/day could be administered without dose-limiting toxicities. Flu-like symptoms and headaches were common and poorly tolerated at the highest IL-3 dose. Significant increases in neutrophil counts (P = 0.018) were observed following IL-3. Overall, IL-3 administration was associated with a modest, but significant increase in CFU-GM within the bone marrow (P = 0.034). IL-3 administration had no consistent effect on CD34+ cell number within bone marrow. For the entire group, engraftment of neutrophils to greater than 0.5 x 10(9)/l occurred at a median of 21 days (range of 13-63 days) and platelet independence occurred at a median of 17 days (range 11-120 days). When IL-3 dose levels were analyzed separately, engraftment of neutrophils and platelets, blood product (platelets and packed RBCs) utilization, and discharge date were not superior in those treated with the higher dose (15.0 micrograms/kg) of IL-3. While higher doses of IL-3 were associated with more toxicity, they did not appear to enhance the stem cell pool or speed engraftment later. The effects of pre-bone marrow harvest IL-3 are modest and likely not as impressive as other approaches aimed at enhancing hematologic recovery following high-dose chemotherapy.
Sosman
J A
JA
Division of Hematology/Oncology, Loyola University Medical Center, Maywood, IL 60153, USA.
Stiff
P J
PJ
Bayer
R A
RA
Peliska
J
J
Peace
D J
DJ
Loutfi
S
S
Stock
W
W
Oldenburg
D
D
Unverzagt
K
K
Bender
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007377:Interleukin-3 / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*
D007377:Interleukin-3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor