Frequency of Agranulocytosis and Mild Neutropenia During Deferiprone Therapy in Clinical Practice

Abstract

996 The incidence of agranulocytosis during deferiprone (Ferriprox®) use has been reported in clinical trials where patients' neutrophil counts were generally monitored weekly and deferiprone was discontinued at the first sign of neutropenia (neutrophil count < 1.5 × 10 9/L), but the incidence in a less rigorously monitored environment is unknown. This observational, open label, prospective, multi-centre, non-interventional drug surveillance program was designed to assess how the safety of deferiprone therapy is monitored in clinical practice. All patients in the 15 participating treatment sites (Egypt, Oman, Saudi Arabia and Turkey) who initiated therapy with deferiprone during the observation period, were enrolled in the program. There were no exclusion criteria. The program was approved by local ethics boards and informed consent was obtained. 294 patients (53.4% males) were enrolled and the results of the first year of treatment are reported herein. Mean (SD) age of all patients was 12.2 ± 10.1 years (range 1 to 52 years old). 224 (76%) were children (93 of which were 1–5 years; 83 were 6–11 years and 48 were 12–17 years old). The majority of the patients had a diagnosis of Thalassemia Major (N= 261). The other patients had Thalassemia Intermedia (N=17), Sickle Cell Disease (N=9), Spherocytosis (N=3), Red Cell Aplasia/Diamond Blackfan Anemia (N=2), Immune Hemolytic Anemia (N=1) or Sideroblastic Anemia (N=1). Deferiprone was initiated as monotherapy (20 to 100 mg/kg/day) in 247 patients or added to deferoxamine therapy in 41 patients or to deferasirox in 6 patients. Serum ferritin was the common measure of iron overload in all 294 patients. Measurement of cardiac (CIC) and liver iron content (LIC) were conducted within 1 year prior to enrollment in 16 patients. Frequency of those measurements and the technique for those assessments varied among participating centers. CIC and LIC were assessed in 14 patients during the first year of follow up. At completion of 1 year of observation, the mean serum ferritin of the 282 patients who had a baseline and at least one follow up assessment had declined from 2858 ± 2481 to 2454 ± 2074 μg/L (p<0.0001). Monitoring of the neutrophil count was conducted at an average interval of 5 ± 4 weeks (1 week to 6 months). One patient (0.3%) experienced agranulocytosis, which resolved with G-CSF 8 days after discontinuation of deferiprone. Ten patients (3.4%) experienced neutropenia (neutrophil count <1.5 × 109/L but not <0.5 × 109/L). One neutropenia was related to acute myeloid leukemia (AML). Deferiprone therapy was interrupted at diagnosis of AML, considered not related to DFP; and the patient was withdrawn from the program. Two patients had two episodes of neutropenia. All neutropenias, except the one associated with AML, resolved within 51 ± 48 days (range 8 to 167 days). Deferiprone therapy was continued in 7 episodes of neutropenia (time for resolution was 28 ± 24 days (range 8 to 67 days)). Deferiprone was interrupted in the remaining 4 episodes (time for resolution was 93 ± 55 days (range 35 to 167 days). None of the neutropenias progressed to agranulocytosis. The data from this observational study indicate that less frequent monitoring of the neutrophil count and continued deferiprone therapy during neutropenia was not associated with prolonged duration of the neutropenia or progression to agranulocytosis. Further evaluation of this observation is warranted. Disclosures: Elalfy: ApoPharma Inc.: Research Funding. Off Label Use: In USA, FERRIPROX® (deferiprone) is an iron chelator indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Shebl:ApoPharma Inc.: Research Funding. Badr:ApoPharma Inc.: Research Funding. Elsafy:ApoPharma Inc.: Research Funding. Salama:ApoPharma Inc.: Research Funding. Al-Tonbary:ApoPharma Inc.: Research Funding. Abdel Rahman:ApoPharma Inc.: Research Funding. Qari:ApoPharma Inc.: Research Funding. Al Damnhouri:ApoPharma Inc.: Research Funding. Al Hawsawi:ApoPharma Inc.: Research Funding. Wali:ApoPharma Inc.: Research Funding. Yesilipek:ApoPharma Inc.: Research Funding. Kilinc:ApoPharma Inc.: Research Funding. Yazman:ApoPharma Inc.: Research Funding. Karakas:ApoPharma Inc.: Research Funding. Tricta:ApoPharma Inc.: Employment.

Deferiprone for transfusional iron overload in sickle cell disease and other anemias: open-label study of up to 3 years

“…In the FIRST-EXT study, the onset of 2 cases of agranulocytosis occurred at a later time point than previously observed in patients enrolled in clinical trials and reported in postmarketing experience, whereby most cases of agranulocytosis occur within the first year of deferiprone therapy. 4 , 21 , 24 Both cases of agranulocytosis in this study resolved despite continuation of deferiprone therapy in 1 case. Data from other studies suggest that agranulocytosis is separate and distinct from episodes of milder neutropenia during deferiprone use.…”

Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study

“…30 Typically occurring in the first year of treatment, agranulocytosis has been reported in approximately 1% to 2% of patients with thalassemia syndromes treated with deferiprone, and less severe episodes of neutropenia in approximately 5% of patients treated with deferirprone. 8,[31][32][33] Agranulocytosis is often related to deferiprone treatment; however, milder cases of neutropenia may not be drug-related and may occur with other chelators with similar incidence to that of deferiprone, as observed in a large randomized controlled trial. 34 In our study, agranulocytosis occurred in 1 (0.7%) deferiprone-treated patient and milder neutropenia in 4 (2.6%) deferiprone-treated patients.…”

Regional consensus opinion for the management of Beta thalassemia major in the Arabian Gulf area

“…Although the international guidelines recommend the use of deferiprone after the age of 6 years, in some Arabian Gulf countries the syrup formulation has been widely used with good efficacy for children 2 years and above with no serious complications. In a recent study, continued deferiprone therapy during episodes of mild neutropenia (down to 1×10 9 /L) has not been associated with progression to agranulocytosis [ 63 ]. We recommend giving extensive counseling to the patients, with clear instructions to report to hospital emergency in case of fever and to have an urgent CBC with ANC count.…”