COMMENTARY

Deferasirox for Porphyria Cutanea Tarda

Graeme M. Lipper, MD

Disclosures

June 28, 2012

Deferasirox for Porphyria Cutanea Tarda: A Pilot Study

Pandya AG, Nezafati KA, Ashe-Randolph M, Yalamanchili R
Arch Dermatol. 2012 May [Epub ahead of print]

Study Summary

Porphyria cutanea tarda (PCT) is the most common porphyria, a group of acquired or genetic disorders of heme biosynthesis with cutaneous and/or systemic manifestations.[1] Classic PCT presents with skin burning, blistering, fragility, dyschromia, atrophic changes, and milia in a photodistribution. Both genetic and acquired forms share the same clinical features, although acquired PCT is far more common and often associated with liver disease (eg, hepatitis C, alcohol-induced hepatitis, hemochromatosis). Treatment with serial phlebotomies to reduce iron load is effective at reducing the skin symptoms of PCT, but phlebotomy is time-consuming and may be problematic in patients with anemia, cardiovascular disease, or infectious diseases such as HIV.

Deferasirox (Exjade®; Novartis Pharmaceuticals Corporation; East Hanover, New Jersey) is an oral, iron-chelating drug that is US Food and Drug Administration-approved for the treatment of iron overload due to chronic blood transfusions.[2,3] A previous off-label study showed clinical benefit in a small group of patients with PCT treated with iron chelation therapy, but the agent used in this study (desferrioxamine) required slow intravenous or subcutaneous infusion over 6-8 hours, rendering this option impractical.[4] Because deferasirox is administered orally, it may be a convenient alternative to serial phlebotomy. To test this possibility, Pandya and colleagues conducted a small pilot study to assess the safety and efficacy of deferasirox for the treatment of PCT (Note: This is an off-label use of the drug).

The investigators enrolled 10 patients with clinically confirmed PCT to receive 6 months of oral deferasirox, initially dosed at 250 mg/day and increased to 500 mg/day as needed (if new blisters formed after 2 months of therapy). The primary outcome measure was a reduction in the number of cutaneous blisters. Additional outcome measures included drops in urinary porphyrin and blood ferritin levels. Study exclusion criteria included family history of porphyrias, personal or family history of renal dysfunction, significant liver function test abnormalities at baseline, or good control of PCT symptoms with serial phlebotomies alone. Two patients dropped out of the study for non-treatment-related reasons.

Result highlights are as follow:

  • Of the 8 patients who completed 6 weeks of deferasirox treatment, 7 showed complete resolution of blistering; the remaining patient showed marked reduction in blister count.

  • Clinical improvement correlated with a reduction in total 24-hour urinary porphyrin and blood ferritin levels.

  • No adverse effects, laboratory abnormalities, or changes in auditory or ophthalmologic evaluations (potential side effects of deferasirox) were noted.

Viewpoint

PCT is a chronic blistering disorder caused by the accumulation of photosensitizing porphyrins in the skin. The underlying defect -- reduced activity of the enzyme uroporphyrinogen decarboxylase -- may be genetic (affecting all cells) or acquired (primarily affecting hepatocytes). Pandya and colleagues found that 6 of 8 patients tested positive for hepatitis C infection, although all cases were judged to be inactive according to viral load and liver function tests. Hence, one cannot extrapolate the encouraging results of this pilot study to patients with familial PCT. Furthermore, the small pilot study design did not allow for the inclusion of control or alternative treatment (eg, phlebotomy) groups. This last point is especially important, because phlebotomy, when feasible, remains the gold standard for treating PCT.

Future studies should therefore:

  • Aim to compare the effectiveness of deferasirox with phlebotomy and antimalarial agents;

  • Assess the long-term safety of chronic iron chelation therapy;

  • Determine the optimum dosing strategy for deferasirox; and

  • Consider the possibility of using iron chelation therapy in conjunction with less frequent phlebotomies to reduce the potential toxicities and/or inconvenience of both treatments.

Abstract

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