Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4872-4873
CORRESPONDENCE
Methemoglobinemia Secondary to Clofazimine Treatment for Chronic
Graft-Versus-Host Disease
 |
LETTER |
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.1
A 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.2
Meanwhile, because conventional agents have been associated with
significant therapy-related complications, several alternative
approaches have been reported in the treatment of cGVHD.4,5
Lee 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lesions relapsed after clofazimine treatment was withdrawn and she was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.
Vaneuza de A. Moreira
Bruno C. De
Medeiros
Carmen M.S. Bonfim
Ricardo Pasquini
Carlos R. De
Medeiros
Serviço de Transplante de Medula
Óssea
Hospital de Clínicas
UFPR
Curitiba,
Brazil
| |
REFERENCES |
1.
Atkinson K:
Chronic graft-versus-host disease.
Bone Marrow Transplant
5:69, 1990[Medline]
[Order article via Infotrieve]
2.
Sullivan KM, Witherspoon RP, Storb R, Deeg HJ, Dahlberg S, Sanders JE, Appelbaum FR, Doney KC, Weiden P, Anasetti C, Loughran TP, Hill R, Shields A, Yee G, Shulman H, Nims J, Strom S, Thomas ED:
Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-versus-host disease.
Blood
72:555, 1988[Abstract/Free Full Text]
3.
Sullivan KM, Witherspoon RP, Storb R, Weiden P, Flournoy N, Dahlberg S, Deeg HJ, Sanders JE, Doney KC, Appelbaum FR, McGuffin R, McDonald GB, Meyers J, Schubert MM, Gauvreau J, Shulman H, Sale GE, Anasetti C, Loughran TP, Strom S, Nims J, Thomas ED:
Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-versus-host disease: Prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation.
Blood
72:546, 1988[Abstract/Free Full Text]
4.
Parker PM, Chao N, Nademanee A, O'Donnell MR, Schmidt GM, Snyder DS, Stein AS, Smith EP, Molina A, Stepan DE, Kashyap A, Planas I, Spielberger R, Somlo G, Margolin K, Zwingenberger K, Wilsman K, Negrin RS, Long GD, Niland JC, Blume KG, Forman SJ:
Thalidomide as salvage therapy for chronic graft-versus-host disease.
Blood
86:3604, 1995[Abstract/Free Full Text]
5.
Summerfield GP, Bellingham AJ, Bunch C, Woodrow JC:
Successful treatment of chronic cutaneous graft-versus-host disease (GVHD) with penicillamine.
Clin Lab Haematol
5:313, 1983[Medline]
[Order article via Infotrieve]
6.
Lee SJ, Wegner AS, Mcgarigle CJ, Bierer BE, Antin JH:
Treatment of chronic graft-versus-host disease with clofazimine.
Blood
89:2298, 1997[Abstract/Free Full Text]
7.
Benz EJ Jr:
Hemoglobin variants associated with hemolytic anemia, altered oxygen affinity, and methemoglobinemias, in
Hoffman R,
Benz EJ Jr,
Shattil SJ,
Furie B,
Cohen HJ,
Silberstein LE
(eds):
Hematology: Basic Principles and Practice. New York, NY, Churchill Livingstone, 1995, p 648.
8.
Queiroz RH, Melchior E Jr, de Souza AM, Gouveia E, Barbosa JC, Carvalho D:
Haematological and biochemical alterations in leprosy patients already treated with dapsone and MDT.
Pharm Acta Helv
72:209, 1997[Medline]
[Order article via Infotrieve]
9.
Hoetelmans RM, Otten JM, Koks CH, Soesan M, Beijnen JH:
Combined dapsone and clofazimine intoxication.
Hum Exp Toxicol
15:625, 1996[Abstract/Free Full Text]
10.
Toktamysova ZS, Kairakbaeva GM:
The effect of phenazine methosulfate on human erythrocytes.
Biofizika
39:681, 1994[Medline]
[Order article via Infotrieve]
11.
Minetti M, Mallozzi C, Scorza G, Scott MD, Kuypers FA, Lubin BH:
Role of oxygen and carbon radicals in hemoglobin oxidation.
Arch Biochem Biophys
302:233, 1993[Medline]
[Order article via Infotrieve]
12.
Bartal M, Mazor D, Dvilansky A, Meyerstein N:
Iron deficiency anemia: Recovery from in vitro oxidative stress.
Acta Haematol
90:94, 1993[Medline]
[Order article via Infotrieve]
13.
Lukens J:
Methemoglobinemia and other disorders accompanied by cianosis, in
Lee G,
Bithell T,
Foerster J,
Athens J,
Lukens J
(eds):
Wintrobe's Clinical Hematology, vol 1. Philadelphia, PA, Lea & Febiger, 1993, p 1262.
