Clozapine-induced leukopenia: arguments for rechallenge

Abstract

The report of clozapine-induced late leukopenia by Latif et al. [1] adds to the body of literature on this rare but important subject [2–5]. We would like to comment on this case report and draw attention to the differences between guidelines on this subject. In line with the two most influential international guidelines, the European Medicines Agency (EMEA) [6] and the Food and drug Administration (FDA) [7], clozapine was withdrawn when the white blood count (WBC) was 2.80 9 10/l, below the accepted threshold of 3.0 9 10/l. Interestingly, while the EMEA states that clozapine must be stopped and never prescribed again when the white blood count (WBC) is \3.0 9 10/l or the neutrophil count (NTC) is\1.5 9 10/ l, the FDA leaves the possibility open for a rechallenge with clozapine if the WBC remains [2.0 9 10/l and the NTC [1.0 9 10/l. The risk of serious complications during close monitoring is limited: an NTC of 1.0–1.5 9 10/l is not accompanied by an increased risk of infection, and the risk is only slightly increased when the NTC is 0.5–1.0 9 10/l; however, infections are common when the NTC is 0.2–0.5 9 10/l and almost inevitable when the NTC drops below 0.2 9 10/l [8]. The patient described in the case report had only moderate leukopenia and mild neutropenia. Moreover, low NTC is not always a sign of a malign process and can present as ‘‘pseudo-neutropenia’’ or benign neutropenia. Pseudo-neutropenia has several causes, varying from a laboratory fault, extreme use of neutrophils due to a viral infection, diurnal variation (low NTC in the morning, higher NTC in the afternoon), and ethnicity (NTC levels are low in individuals of African or Yemenite Jewish descent). Although the case report does not provide sufficient information to determine whether these factors were taken into account, we assume they were. The more prevalent benign neutropenias are characterised by a rapid recovery of cell numbers (NTC and WBC) after discontinuation of clozapine therapy. The condition is readily reversible without residual symptoms. In contrast, a malign process is more severe, with a continuous decrease in NTC and WBC even after discontinuation of clozapine, as a result of the depletion of leukocyte precursors in the bone marrow by an as yet unknown process associated with clozapine therapy; it takes time for the bone marrow to recover. We were unable to decide which type of neutropenia was present from the information available in this case. The authors are members of the board of the Netherlands Clozapine Collaboration Group.