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Fatal All-Trans Retinoic Acid Pneumonitis
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IN RESPONSE:
Smith-Whitley and Lange raise several important points. First, the “retinoic acid syndrome” is a constellation of clinical signs (fever, weight gain, pulmonary infiltrates, and pleural effusions) that can mimic various illnesses to which patients with acute promyelocytic leukemia (APL) are susceptible, especially congestive heart failure and infectious pneumonia [1]. (Indeed, our housestaff has identified two recent patients who presented with the “syndrome” before treatment was initiated.) Second, this complex by no means accounts for all idiosyncratic drug-related effects observed in patients with APL; variations have included pericarditis and high spiking fevers without an apparent infectious source, both of which also appear to be responsive to steroids. Third, the use of high-dose corticosteroids modifies the course of this syndrome in many—but certainly not all—patients. Fourth, children are extraordinarily sensitive to the central nervous system effects of all-trans retinoic acid (TRA) and tolerate only a fraction of the dose that can be administered to adults [2]. The French experience suggests that patients with APL have responded to TRA doses of 15 mg/m2 (Degos L. Personal communication). Because intracranial hypertension is dose-related rather than idiosyncratic in children, further study of their dose-response is warranted. Fifth, although the cause of TRA-induced leukocytosis is unclear, worsening of the coagulopathy is unusual.
Most importantly, their experience re-emphasizes that most patients with TRA-induced leukocytosis do not develop symptoms of the “TRA syndrome”; therefore, treatment with cytotoxic drugs specifically directed at the leukocyte count risks exacerbation of the coagulopathy. For the next year or so, we strongly suggest that practitioners eschew compassionate treatment requests for this drug and continue to refer patients to major centers until this important safety issue is resolved.
Raymond P. Warrell Jr.
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should:
•Include no more than 300 words of text, three authors, and five references
•Type with double-spacing
•Send three copies of the letter, an authors' form signed by all authors, and a cover letter describing any conflicts of interest related to the contents of the letter.
Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
Annals welcomes electronically submitted letters.
- Copyright ©2004 by the American College of Physicians
