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Toxic skin eruption induced by fludarabine
European Journal of Internal Medicine 14 (2003) 134–135 www.elsevier.com / locate / ejim
Letter to the editor
Toxic skin eruption induced by fludarabine Brigitte Granel a , Jacques Serratrice a , Nicoleta Ene a , Marie-Christine Rojat-Habib b , ´ Bouabdallah c , Patrick Disdier a , *, Pierre-Jean Weiller a Reda a
´ Service de Medecine Interne, CHU Timone, 264 rue Saint-Pierre, 13385 Marseille Cedex 5, France Service d’ Anatomie Pathologique, CHU Timone, 264 rue Saint-Pierre, 13385 Marseille Cedex 5, France c ´ Institut Paoli-Camettes, Boulevard de Sainte-Marguerite, 13009 Marseille, France Service d’ Hematologie b
Received 5 November 2002; received in revised form 5 November 2002; accepted 7 November 2002
Fludarabine is one of the most effective single agents for the treatment of low-grade lymphoid malignancy, particularly chronic lymphocytic leukemia (CLL). We present here an unusual skin reaction occurring after fludarabine treatment for a CLL. A 61-year-old man had an untreated CLL (Binet stage A) since 1988. In 1996, faced with enlarged, diffuse, abdominal lymphadenopathies, splenomegaly, and an increased white blood cell count (132310 9 / l, with 98% lymphocytes), sequential fludarabine treatment was started. In July 1996, intravenous fludarabine 50 mg / day was administered for 5 days. Six days later, the patient presented with vesicular and erythematous lesions on his scalp and trunk without pruritus or fever. As bullae appeared on his lower limbs, he was admitted to the hospital 2 weeks later. Physical examination revealed cervical and thoracic erythematous vesicles, together with some bullae on the lower limbs of different onset. His white blood cell count was 18.5310 9 / l with 78% lymphocytes. C-reactive protein was below 3 mg / l. A search for cryoglobulinemia and antinuclear antibodies was negative. Serological tests for cytomegalovirus, varicellae-zoster virus, and human immunodeficiency virus were negative. The patient did, however, have antibodies against herpes simplex and Epstein–Barr viruses. Histological examination of a bulla revealed an intraepidermic detachment, disappearance of the normal layers of epithelial cells, and exocytosis of mononuclear * Corresponding author. Service de Medecine ´ Interne du Professeur ˆ P.-J. Weiller, Hopital de la Timone, 13385 Marseille Cedex 5, France. Tel.: 133-491-38-6039; fax: 133-491-34-7401. E-mail address: [email protected] (P. Disdier).
cells. The roof was characterized by necrosis at the center. In the bullae, there was fibrin, necrotic epithelial cells, and a polymorphonuclear cell infiltrate. In the dermis, there was a diffuse inflammatory infiltrate located around the capillary vessels and the appendages that was composed of lymphocytes, histiocytes, and rare neutrophils and eosinophils. Expansion of this inflammatory infiltrate into the hypodermis was also noted. Direct immunofluorescence was negative. Culture of the bulla fluid did not provide any evidence of viral infection. A search for circulating antiintercellular substance and anti-basal membrane antibodies was negative. The diagnosis of a drug-induced toxic reaction to fludarabine was made. The treatment was definitively stopped and the lesion regressed completely after 1 month. No recurrence was observed at the last clinical evaluation in 1999. Given the amount of time between the onset of the treatment and that of the skin lesions, the absence of recurrence after fludarabine withdrawal, and the absence of other causes, we assume that fludarabine treatment was probably the cause of this skin reaction. Toxic skin eruptions associated with fludarabine treatment are rare and include rashes and, on very rare occasions, StevensJohnson and Lyell syndromes [1]. Nomdedeu et al. [2] reported a peculiar acral erythematous eruption after this treatment. Despite its immunosuppressive properties, fludarabine can induce autoimmune disorders such as autoimmune hemolytic anemia or autoimmune thrombocytopenia and mucocutaneous autoimmune syndrome. Paraneoplastic pemphigus following treatment of CLL with fludarabine has already been described [3,4] and is sometimes lethal [5]. In our observation, Nikolsky sign was absent, there
0953-6205 / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0953-6205(02)00217-0
B. Granel et al. / European Journal of Internal Medicine 14 (2003) 134–135
was no acantholysis, no positivity of direct immunofluorescence, no circulating pemphigus antibodies, and clinical outcome was good after withdrawal of the drug without immunosuppressive therapy. Thus, we conclude that a toxic cutaneous reaction was induced by fludarabine. Such a side effect should be rapidly diagnosed, due to the potential severity of symptoms, and fludarabine treatment should be stopped.
[2]
[3] [4]
[5]
References [1] Goodman ER, Fiedor PS, Fein S, Athan E, Hardy MA. Fludarabine phosphate: a DNA synthesis inhibitor with potent immunosuppres-
135
sive activity and minimal clinical toxicity. Am Surg 1996;62:435– 42. Nomdedeu J, Puig L, Martino R et al. Peculiar acral erythematous eruption after fludarabine treatment. Biol Clin Hematol 1995;17:92– 3. Gooptu C, Littlewood TJ, Frith P et al. Paraneoplastic pemphigus: an association with fludarabine? Br J Dermatol 2001;144:1255–61. Braess J, Reich K, Strutz F, Neumann C, Hiddemann W. Mucocutaneous autoimmune syndrome following fludarabine therapy for lowgrade non-Hodgkin’s lymphoma of B-cell type (B-NHL). Ann Hematol 1997;75:227–30. Bazarbachi A, Bachelez H, Dehen L, Delmer A, Zittoun R, Bubertret L. Lethal paraneoplastic pemphigus following treatment of chronic lymphocytic leukemia with fludarabine. Ann Oncol 1995;6:730–1.
Letter to the editor
Toxic skin eruption induced by fludarabine Brigitte Granel a , Jacques Serratrice a , Nicoleta Ene a , Marie-Christine Rojat-Habib b , ´ Bouabdallah c , Patrick Disdier a , *, Pierre-Jean Weiller a Reda a
´ Service de Medecine Interne, CHU Timone, 264 rue Saint-Pierre, 13385 Marseille Cedex 5, France Service d’ Anatomie Pathologique, CHU Timone, 264 rue Saint-Pierre, 13385 Marseille Cedex 5, France c ´ Institut Paoli-Camettes, Boulevard de Sainte-Marguerite, 13009 Marseille, France Service d’ Hematologie b
Received 5 November 2002; received in revised form 5 November 2002; accepted 7 November 2002
Fludarabine is one of the most effective single agents for the treatment of low-grade lymphoid malignancy, particularly chronic lymphocytic leukemia (CLL). We present here an unusual skin reaction occurring after fludarabine treatment for a CLL. A 61-year-old man had an untreated CLL (Binet stage A) since 1988. In 1996, faced with enlarged, diffuse, abdominal lymphadenopathies, splenomegaly, and an increased white blood cell count (132310 9 / l, with 98% lymphocytes), sequential fludarabine treatment was started. In July 1996, intravenous fludarabine 50 mg / day was administered for 5 days. Six days later, the patient presented with vesicular and erythematous lesions on his scalp and trunk without pruritus or fever. As bullae appeared on his lower limbs, he was admitted to the hospital 2 weeks later. Physical examination revealed cervical and thoracic erythematous vesicles, together with some bullae on the lower limbs of different onset. His white blood cell count was 18.5310 9 / l with 78% lymphocytes. C-reactive protein was below 3 mg / l. A search for cryoglobulinemia and antinuclear antibodies was negative. Serological tests for cytomegalovirus, varicellae-zoster virus, and human immunodeficiency virus were negative. The patient did, however, have antibodies against herpes simplex and Epstein–Barr viruses. Histological examination of a bulla revealed an intraepidermic detachment, disappearance of the normal layers of epithelial cells, and exocytosis of mononuclear * Corresponding author. Service de Medecine ´ Interne du Professeur ˆ P.-J. Weiller, Hopital de la Timone, 13385 Marseille Cedex 5, France. Tel.: 133-491-38-6039; fax: 133-491-34-7401. E-mail address: [email protected] (P. Disdier).
cells. The roof was characterized by necrosis at the center. In the bullae, there was fibrin, necrotic epithelial cells, and a polymorphonuclear cell infiltrate. In the dermis, there was a diffuse inflammatory infiltrate located around the capillary vessels and the appendages that was composed of lymphocytes, histiocytes, and rare neutrophils and eosinophils. Expansion of this inflammatory infiltrate into the hypodermis was also noted. Direct immunofluorescence was negative. Culture of the bulla fluid did not provide any evidence of viral infection. A search for circulating antiintercellular substance and anti-basal membrane antibodies was negative. The diagnosis of a drug-induced toxic reaction to fludarabine was made. The treatment was definitively stopped and the lesion regressed completely after 1 month. No recurrence was observed at the last clinical evaluation in 1999. Given the amount of time between the onset of the treatment and that of the skin lesions, the absence of recurrence after fludarabine withdrawal, and the absence of other causes, we assume that fludarabine treatment was probably the cause of this skin reaction. Toxic skin eruptions associated with fludarabine treatment are rare and include rashes and, on very rare occasions, StevensJohnson and Lyell syndromes [1]. Nomdedeu et al. [2] reported a peculiar acral erythematous eruption after this treatment. Despite its immunosuppressive properties, fludarabine can induce autoimmune disorders such as autoimmune hemolytic anemia or autoimmune thrombocytopenia and mucocutaneous autoimmune syndrome. Paraneoplastic pemphigus following treatment of CLL with fludarabine has already been described [3,4] and is sometimes lethal [5]. In our observation, Nikolsky sign was absent, there
0953-6205 / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0953-6205(02)00217-0
B. Granel et al. / European Journal of Internal Medicine 14 (2003) 134–135
was no acantholysis, no positivity of direct immunofluorescence, no circulating pemphigus antibodies, and clinical outcome was good after withdrawal of the drug without immunosuppressive therapy. Thus, we conclude that a toxic cutaneous reaction was induced by fludarabine. Such a side effect should be rapidly diagnosed, due to the potential severity of symptoms, and fludarabine treatment should be stopped.
[2]
[3] [4]
[5]
References [1] Goodman ER, Fiedor PS, Fein S, Athan E, Hardy MA. Fludarabine phosphate: a DNA synthesis inhibitor with potent immunosuppres-
135
sive activity and minimal clinical toxicity. Am Surg 1996;62:435– 42. Nomdedeu J, Puig L, Martino R et al. Peculiar acral erythematous eruption after fludarabine treatment. Biol Clin Hematol 1995;17:92– 3. Gooptu C, Littlewood TJ, Frith P et al. Paraneoplastic pemphigus: an association with fludarabine? Br J Dermatol 2001;144:1255–61. Braess J, Reich K, Strutz F, Neumann C, Hiddemann W. Mucocutaneous autoimmune syndrome following fludarabine therapy for lowgrade non-Hodgkin’s lymphoma of B-cell type (B-NHL). Ann Hematol 1997;75:227–30. Bazarbachi A, Bachelez H, Dehen L, Delmer A, Zittoun R, Bubertret L. Lethal paraneoplastic pemphigus following treatment of chronic lymphocytic leukemia with fludarabine. Ann Oncol 1995;6:730–1.