Combination Deferasirox and Deferiprone for Severe Iron Overload in Thalassemia

Death and disability from iron related damage to the heart remain the most serious issue
facing transfusion-dependent patients with thalassemia. However, over the past decade there
have been several reports of improved survival and fewer cardiac complications. This
improvement may be related to the availability of three chelators and also the accurate
measurement of iron stores in various organs (e.g. heart and liver) with magnetic resonance
imaging, which allows for personalized, tailored medical care for patients. The chelator
characteristics, side effect profiles, and ability to remove iron from specific organs differ
among the chelators, suggesting that combination therapy may be beneficial. Using two drugs
at lower doses may be more tolerable than escalating doses of a single drug and may improve
iron removal. The combination of deferoxamine and deferiprone has been shown to be
particularly beneficial for reducing cardiac iron, but it requires a painful
injection/infusion, which hinders adherence. This pilot study aims to investigate the safety
of an oral-only combination chelator regimen (deferasirox and deferiprone) in individuals
with thalassemia major with poorly controlled iron overload and to assess how well this
chelator combination lowers iron stores over one year.

Inclusion Criteria:

- Alpha or beta thalassemia

- Receiving chronic transfusions (at least 20 transfusions in lifetime) with iron
overload requiring treatment with chelation

- Serum ferritin >500 ng/ml

- Liver iron concentration equal to or greater than 10 mg/g dw (by R2 MRI) or 7 to 10
mg/g dw (by R2 MRI) and not improving OR cardiac T2* between 6 and <20 ms

- Women of childbearing age must have a negative pregnancy test

- Agree to use approved method of contraception for the duration of the study

- Subjects must have a good understanding of the study and be willing to comply with
study procedures

Exclusion Criteria:

- Subjects with past history of unexplained neutropenia (ANC < 1500/mcL), clinically
significant renal disease (creatinine above the upper limit of normal), proteinuria
>300 mg/L, clinically significant liver disease (ALT > 5x upper limit of normal),
pulmonary or cardiovascular disease

- History of other clinically relevant oral, endocrine, neurologic, psychiatric,
immunologic, bone marrow or skin disorder that contraindicates dosing with deferasirox
or deferiprone

- History of adverse reaction or known allergy to either deferasirox or deferiprone
necessitating drug discontinuation

- Currently receiving treatment for active hepatitis

- Use of any investigational agent in the past 30 days

- Cardiac T2* <6 ms, left ventricular ejection fraction < 56%, and/or arrhythmia
(certain subjects may be eligible if they have already had a trial of deferoxamine and
deferiprone). Subjects who refuse to use deferoxamine after extensive consultation
with at least 2 health care providers will also be allowed to participate.

- Pregnant or breastfeeding females

- Unwilling or unable to comply with study related procedures