CYTOKINE INTERVENTION PERMITS DOSE-ESCALATION OF RADIOANTIBODY - AN ANALYSIS OF MYELOSTIMULATION BY BOLUS VERSUS CONTINUOUS-INFUSION OF IL-1 GM-CSF/

Background. The authors recently reported that a 12-day schedule (begi nning 3 days before radioantibody treatment) of twice-daily dosing of rH-IL-1 (1 X 103 U/ dose) and rM-GM-CSF (0.5 mu g/dose) can reduce the magnitude and duration of radioantibody-induced myelosuppression, the reby permitting a 25-30% increase in the dose of radioantibody that ca n be administered without the dose proving lethal. In an effort to fur ther reduce toxicity and escalate the tolerated dose, the authors alte red the method of administration of cytokines from daily bolus dosing to continuous infusion by implantable osmotic pumps. Methods. A contro l group of mice was compared to five groups of mice that either did or did not receive a 340 mu Ci dose of radioantibody, and received no cy tokines, cytokines by bolus dosing, or cytokines by continuous infusio n. For 4 weeks, peripheral white blood cell and thrombocyte counts and thymus and spleen weights were taken, marrow cell number was monitore d, and marrow colony-forming unit activity was evaluated weekly in the untreated control mice and the treated mice. Results. These studies d emonstrated that after a dose of radioantibody, continuous dosing of c ytokines resulted in higher white blood cell (WBC) and platelet val-ue s than if bolus delivery was used (day 7, WBC: 110% vs. 59%; day 14, W BC: 85% vs. 62%; day 21, WBC: 98% vs. 42%; day 7, platelets: 122% vs. 51%; day 14, platelets: 159% vs. 72%; day 21, platelets: 239% vs. 171% ). A comparison of bolus versus continuous dosing in the absence of ra dioantibody indicated that spleen weight increased by 40-60% after con tinuous infusion of cytokines and by 20-25% after bolus dosing. The 20 -30% decrease in thymus weight was similar with both dosing regimens. Colony-forming units (CFUs) in marrow increased from 30-35 in untreate d mice to 50-55 in mice given cytokines by bolus injection, and to 150 -180 in mice given continuous infusion of cytokines. Spleen CFUs exhib ited an insignificant increase after bolus dosing of cytokines but inc reased almost fourfold after continuous dosing. Peak stimulation of ma rrow and spleen CFUs occurred 28 days after initiation of cytokine adm inistration (2 weeks after cytokines administration was stopped). The probability of survival for 6 weeks after further dose escalation to 3 60 mu Ci I-131-MN-14 immunoglobulin G was 16.4% +/- 8.6% after bolus d osing and 58.1% +/- 11.3% after continuous infusion of cytokines. Conc lusions. Although continuous infusion of cytokines proved to be a bett er method of reducing hematopoietic toxicity, further dose escalation of radioimmunotherapy using the ''pump'' method of cytokine delivery w as not possible. Cytokine intervention by either mode of delivery perm its a 25% dose intensification without the dose becoming lethal. Furth er escalation is not feasible, possibly because of other end organ tox icity. Cancer 1994; 73:1083-92.