Toxic epidermal necrolysis following combination of methotrexate and trimethoprim-sulfamethoxazole

A 15-year-old boy with T-cell acute lymphoblastic leukemia (ALL) (FAB L1), diagnosed in 1995, received combination chemotherapy consisting of 6 weeks of induction (vincristine, epirubicin, L-asparaginase, prednisolone) and 2 weeks of consolidation (cytosine arabinosides, etoposide). After achieving remission, for further maintenance of remission, he was treated with 14 cyc les of intensive chemotherapy consisting of 6-MP, 10 mg/kg orally on the fi rst 4 days, and cyclophosphamide, 1200 mg/m(2), vincristine, 1.5 mg/m(2), e pirubicin, 15 mg/m(2), and cytosine arabinoside, 40 mg/m(2), intravenously on days 4, 11, 39, and 40, respectively. On day 18 of each cycle, he receiv ed intravenous methotrexate (MTX) infusion in a total dose of 150 mg/m(2) p lus oral leucovorin (30 mg/m(2)) rescue 36 h after starting MTX therapy. In addition, oral trimethoprim-sulfamethoxazole was given regularly to preven t Pneumocystis carinii infection. The patient achieved remission during the first course of treatment, but 8 months later the disease relapsed. He then received four doses of MTX (800 mg intravenously) plus leucovorin rescue in the following 4 months. During the last MTX therapy, small hemorrhagic bullae were found on the lateral si de of the right ankle, but subsided after a few days. Due to partial remission of the disease, he was admitted again in January 1 999 for high-dose MTX therapy. An initial hemogram on admission revealed he moglobin 7.2 g/dl, white cell count 15,200/mm(3), platelet count 153/mm(3), blood creatinine 0.5 mg/dL, and alanine leucine aminotransferase (ALT) 20 U/L. He received 8500 mg of MTX (5000 mg/m(2)) as a continuous intravenous infusion for 24 h. Thirty-six hours after the start of MTX infusion, leucov orin (30 mg, intravenous) rescue was initiated every 6 h for 3 days. Anothe r preventive measure to cover MTX toxicity included aggressive intravenous fluid replacement (4 L/m(2)/day) and the addition of 25 meq/L sodium bicarb onate to the intravenous fluid to alkalinize the urine. Concurrent medicati on included 6-MP (50 mg) once daily and trimethoprim-sulfamethoxazole (120 mg, 600 mg) twice daily every other day. Plasma MTX levels were 52.36 mu mo l/L 24 h after MTX infusion, 1.87 mu mol/L after 48 h, 0.57 mu mol/L after 72 h, and 0.41 mu mol/L after 96 h. These indicated delayed MTX plasma clea rance. The blood creatinine level was mildly elevated from 0.5 mg/dL to 0.7 mg/dL. Thirty-six hours after the administration of MTX, the patient devel oped an erythematous painful swelling on the right middle finger. The eryth ema, with subsequent large bulla formation, progressed to all the fingers, toes, palms, and the soles of the feet. Some erythematous to hemorrhagic pa pules also appeared on the bilateral elbows. Subsequently, diffuse tender e rythema with extensive erosions and focal tiny pustules developed on the ba ck, abdomen, proximal extremities, and face (Figs 1a,b). A positive Nikolsk y's sign was also present. A biopsy specimen of the right dorsal hand lesio n revealed parakeratosis, detached acanthotic epidermis with scattered necr otic keratinocytes, dyskeratotic cells and nuclear atypia, neutrophilic exo cytosis, and many neutrophils in the papillary dermis (Fig. 2). The skin co ndition deteriorated rapidly. Toxic epidermal necrolysis-like lesions invol ved 90% of the total body surface on the fifth day after MTX infusion. Muco sitis, diarrhea, involuntary tremor, fever, and chills were noted. The pati ent was then sent to the burn unit for intensive skin care. Ten days after MTX therapy, profound agranulocytosis and thrombocytopenia (white cell coun t 100/mm(3), platelets 14,000/mm(3), and hemoglobin 5.6 g/dL) were found. T he patient was then started on granulocyte colony stimulation factor (G-CSF , 5 mu g/kg/day), but his general condition deteriorated rapidly and he die d 6 days later due to septic shock and multiple organ failure.