Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Abstract

Use of the iron chelator deferiprone for treatment of iron overload in thalassemia patients is associated with concerns over agranulocytosis, which requires weekly absolute neutrophil counts (ANC). Here, we analyze all episodes of agranulocytosis (n = 161) and neutropenia (n = 250) during deferiprone use in clinical trials (CT) and postmarketing surveillance programs (PMSP). Rates of agranulocytosis and neutropenia in CT were 1.5% and 5.5%, respectively. Of the agranulocytosis cases, 61% occurred during the first 6 months of therapy and 78% during the first year. These events appeared to be independent of dose, and occurred three times more often in females than males. Their duration was not significantly shortened by use of G‐CSF. No patient with baseline neutropenia (n = 12) developed agranulocytosis during treatment, which raises questions about the validity of prior neutropenia as a contraindication to use. Only 1/7 novel neutropenia cases in CT progressed to agranulocytosis with continued treatment, indicating that neutropenia does not necessarily lead to agranulocytosis. The agranulocytosis fatality rate was 0% in CT and 15/143 (11%) in PMSP. Rechallenge with deferiprone produced agranulocytosis in 75% of patients in whom the event had already occurred, and in 10% with previous neutropenia. Weekly ANC monitoring allows early detection and interruption of therapy, but does not prevent agranulocytosis from occurring. Its relevance appears to decrease after the first year of therapy, when agranulocytosis occurs less often. Based upon analysis of data collected over the past 20 years, it appears that patient education may be the key to minimizing agranulocytosis‐associated risks during deferiprone therapy. Am. J. Hematol. 91:1026–1031, 2016. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

Ethnic benign neutropenia: A phenomenon finds an explanation

“…It might also be acceptable to resume therapy when the ANC is at a habitual level. Similar conclusions were reached for the use of deferiprone 43 and are probably valid for other DINPs, although not formally tested.…”

Safety profiles of iron chelators in young patients with haemoglobinopathies

“…However, due to the limitations of meta-analysis of very rare events, we need to consider a pooled incidence up to 0.7% (upper confidence interval). This is in agreement with previous reports and SPCs (56,57,100). Several case reports of non-fatal agranulocytosis in young patients have been published.…”

The Duffy antigen receptor for chemokines, ACKR1,– ‘Jeanne DARC’ of benign neutropenia

“…No increase of infection was noted also in individuals with ethnic neutropenia who develop a clozapine‐induced decrease of the neutrophil count (Manu et al , ), leading to a change in the US Food and Drug Administration (FDA) guidelines, allowing those with benign ethnic neutropenia the opportunity to be commenced on clozapine (Sultan et al , ). A similar approach was adopted for deferiprone (Tricta et al , ), which may be relevant to other drug‐induced neutropenias as well (Palmblad & Hoglund, ).…”