Single-Centre, North American Experience with Compassionate Use of Deferiprone in Patients with Beta-Thalassemia Major,

Deferiprone (DFP) is a thrice daily, oral iron chelator with cardiac-specific properties. It has been demonstrated to improve LV EF% and reduce cardiac related morbidity and mortality in patients with Beta Thalassemia Major (TM). It was approved as second line therapy by European regulatory agencies in 1999, but despite being developed by a Toronto-based pharmaceutical company, has yet to be approved by Health Canada or the FDA. Since July 2004 it has been available via a compassionate use program (CUP). The Red Blood Cell Disorders Program (RBCDP, Toronto General Hospital, Canada) is Canada's largest adult Hemoglobinopathy comprehensive care centre. In mid 2009, the RBCDP took a programmatic decision to systematically enrol those patients with significant cardiac siderosis, and hence at risk of cardiac events and death, in the CUP. Patients intolerant of or having a suboptimal responsive to Deferoxamine or/and Deferasirox were also considered for DFP therapy. Here we report on a single centre experience with this oral chelator within a North American healthcare system.

Approval was received from the Research Ethics Board and data was collected retrospectively from the RBCDP database, electronic patient records, and CUP monitoring records. Patients complied with weekly CBC monitoring through the use of community based laboratories with electronic transmission of results in a timely manner. All patients who were prescribed DFP for at least 12 months between January 2009 and January 2011 were included in the analysis. Efficacy data and adverse events are reported here.

Thirty-four patients were identified (19 females and 15 males; 29 beta-Thalassemia Major, 4 Hemoglobin E/b-Thalassemia compound heterozygote, 1 homozygous sickle cell disease) for a total of 28.72 patient-years observed. 2 patients were excluded from analysis due to incomplete data. Nineteen patients (58%) were splenectomised. Mean age at the start of DFP therapy was 31.07 years (SEM +/− 5.18 years). 16 patients received DFP in combination with another chelator. 22/34 were prescribed DFP for severe cardiac siderosis. Sixteen (48%) of the patients were prescribed at 75 mg/kg/day and 17 (52%) at 100 mg/kg/day. Mean physician-assessed adherence rate was 68% (SEM +/− 12%), with 64% of patients having >90% adherence rate. Serial T2* and ejection fraction (EF) measurements from cardiac MRI were available in 22 patients, with a mean change in T2* of +2.6 ms/year (SEM +/− 0.5 ms/year) and EF +1.5%/year (SEM +/− 0.3%/year). There was a significant change in T2* measurements after an average of 425 days (SEM +/− 91 days) of DFP therapy (P=0.0006). No significant change was observed in LIC (−2.84 mg/g dry weight; P = 0.067) or ferritin values (542.6 umol/L; P=0.327). Neutropenia (ANC < 1.5) was observed in 4 patients totalling 11 instances but no agranulocytosis was observed. Four patients had an asymptomatic transient increase in alanine transferase (> 5x upper limit of normal). Four patients had arthralgias, which resolved with dose reduction.

We believe that the RBCDP currently has the largest active population of patients receiving chelation with DFP in North America. Initial data presented here demonstrates the drug to be effective in controlling cardiac iron overload; is well tolerated; and reveals no new adverse effects. Our experience mirrors that of Thalassemia centres outside of North America over the past 10 years. Longer follow up of this cohort is ongoing.

Off Label Use: Deferiprone is an unlicensed medication in USA and Canada, and is available through compassionate use. It is an oral iron chelator. Kuo:Novartis Canada: Research Funding.