Methemoglobinemia Secondary to Clofazimine Treatment for Chronic Graft-Versus-Host Disease

To the Editor:

Chronic graft-versus-host disease (cGVHD) is a frequent late complication of allogeneic bone marrow transplantation (allo-BMT), affecting 20% to 50% of long-term transplant survivors.1A wide combination of agents have been used as primary therapy for extensive cGVHD,2,3 but none has proved to be completely effective against extensive multiorgan involvement.2Meanwhile, because conventional agents have been associated with significant therapy-related complications, several alternative approaches have been reported in the treatment of cGVHD.4,5Lee et al6 have recently reported their successful experience with clofazimine as treatment to skin involvement, flexion contratures, or oral manifestations for patients with cGVHD. Mild gastrointestinal side effects and red-brown hyperpigmentation of the skin and conjuntiva were the only complications noted.6 We report a case of acquired methemoglobinemia (metHb) secondary to clofazimine treatment for cGVHD after allo-BMT.

An 8-year-old girl with severe aplastic anemia received an HLA-identical allo-BMT prepared with busulphan and cyclophosphamide. GVHD prophylaxis was cyclosporine (CSA) and methotrexate. She developed an extensive progressive cGVHD, which included lichenoid lesions of buccal mucosa and oral dryness in addition to skin involvement and liver dysfunction. She was managed with CSA at 175 mg/d, prednisone at 30 mg/d, and thalidomide at 300 mg/d. On day +333, buccal mucosa lesions persisted, so thalidomide was substituted for clofazimine at 300 mg/d. The oral lesions improved significantly during the next 13 days, when she presented with dizziness, malaise, confusion, and peripheral cyanosis, but surprisingly she did not appear to be in any respiratory distress. Her chest x-ray was normal and arterial blood gases showed 99% oxyhemoglobin saturation on 3 L of oxygen by nasal cannula and a methemoglobin level of 33% (control, 3%). Clofazimine treatment was discontinued and the patient managed with methylene blue at 1 mg/kg and ascorbic acid. One hour later, her methemoglobin levels decreased to 7% (control, 2%). Unfortunately, the buccal mucosa lesions relapsed after clofazimine treatment was withdrawn and she was maintained on CSA and prednisone.

Clofazimine is an antymycobacterial agent that has been used in the treatment of leprosy and Mycobacterium avium complex, and has been reported to be useful in several immune-mediated skin disorders.6 Its mechanism of action is unknown, but its immunomodulatory effect is thought to reflect functional inhibition of pathogenic T lymphocytes. Recently, clofazimine has been reported to have encouraging efficacy in the treatment of cGVHD6 in addition to a reduced infection risk, especially in patients with sclerodermatous skin, joint, and oral involvement.

Methemoglobin results from oxidation of the iron moieties in hemoglobin from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state and becomes incapable of binding and transporting oxygen. A diagnosis of MetHb is made when more than 1% of hemoglobin exists in the oxidized (Fe³⁺) form. The condition may be congenital or acquired, and several drugs and chemicals have been reported to induce metHb.7 Therefore, exogenous electron carriers, such as methylene blue, can serve as pharmacologic agents for the treatment of metHb.

Clofazimine’s chemical structure is 3-(p-chloroanilino)-10(p-chlorophenyl)-2,10-dihydro-2-isopropyliminophenazine . Despite reports describing otherwise,8,9 the clofazimine molecule contains two radicals reported to mediate iron hemoglobin oxidation. The first molecule is 3-p-chloroanilino (aniline dye), a para-aminophenol derivative with low anti-inflammatory actions, long known for its hemoglobin-oxidating capacities.7 The second radical, isopropyliminophenazine, a pyrazolon derivative, has also had its hemoglobin iron oxidation properties extensively reported in the literature,10-12 especially under hypoxic conditions.11,12 Its mechanism of action seems to be related to the reduction of gluthatione peroxidase and catalase, originating methemoglobin.13 To the best of our knowledge, this is the first report of metHb secondary to clofazimine therapy.

Because clofazimine is a new drug in this setting, with a potentially broader utilization as first-line treatment due to its encouraging efficacy and lack of infectious complications, physicians must be aware of this rare and reversible, but potentially dangerous adverse reaction.