Do white-cell count spikes predict agranulocytosis in clozapine recipients?

The use of clozapine is limited by the risk of agranulocytosis. The incidence of agranulocytosis after 1 year was .80 percent in 11,555 patients registered in the Clozaril Patient Management System (CPMS) who received clozapine from February 1990 to April 1991. We noticed a tendency for white-cell counts to spike upward before agranulocytosis occurred. We analyzed the CPMS data to test whether a white-cell count spike at least 15 percent above the previous measurement predicted agranulocytosis within 75 days, with a 21-day lag to allow white-cell counts to decline to levels indicative of agranulocytosis. The occurrence of a spike, entered as a time-dependent covariate in proportional hazards regression, significantly predicted development of agranulocytosis (risk ratio, 3.02; 95% confidence interval, 1.38 to 6.57). Spikes were sensitive though nonspecific predictors, occurring frequently in patients who did not develop agranulocytosis. These results, while exploratory, indicate the potential usefulness of these spikes as guidelines to govern the use of clozapine.