Once ATRA syndrome has developed, addition of low-dose CT is ineffective in lowering WBC counts, and leukapheresis is unable to reverse symptoms. Two different approaches aimed at preventing or treating early ATRA syndrome are proposed. One of them, mainly used by the European and Japanese groups [33, 37,109], consists of adding CT from the onset of ATRA in patients presenting with high WBC counts (WBC greater than 5,000/mm3 in the European trial, or greater than 3,000/mm3 in the Japanese trials) or when increases in the WBC counts are seen with ATRA. This approach has been associated with a low incidence of fatal ATRA syndrome. A disadvantage of this approach is that about two-thirds of the patients treated with ATRA also received early CT. However, several reports have shown that the period of neutropenia and thrombocytopenia is significantly shorter in patients who receive CT while already on ATRA, by comparison with CT alone [37, 115]. Furthermore, intensive CT, if not administered early, would have to be administered later on, as consolidation treatment. The possibility, suggested by the European APL 93 trial, that early onset of CT (ATRA+CT) reduces the incidence of relapse, by comparison to ATRA followed by CT (ATRA CT), could be an additional argument for the early onset CT, even in the absence of high WBC counts. This attitude is now a standard approach for the Spanish PETHEMA and Italian GIMEMA groups. Also, of note is that, in APL 93 trial, there were significantly fewer cases of ATRA syndrome in patients who received ATRA+CT as compared to those treated by ATRA CT (y%) [44,116].
By contrast, the usual U.S. approach is to prevent ATRA syndrome by highdose intravenous corticosteroids (dexamethasone, 10 mg IV twice daily for 3 days or more) as soon as the first symptoms occur. This attitude proved effective in the U.S. Intergroup study, both for preventing ATRA syndrome and reducing its mortality .
Finally, there is a consensus concerning the fact that patients presenting with high WBC counts (e.g., more than 15,000-20,000/mm3) will very often develop severe ATRA syndrome with ATRA alone, and require CT and intravenous dexamethasone from the onset of treatment. Some of these patients even present with symptoms analogous to those of ATRA syndrome at diagnosis . The same recommendations that apply to ATRA syndrome during treatment with ATRA apply to the similar syndrome observed after treatment with arsenic derivatives.
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