Recent Advances in the Biology and Treatment of Acute Promyelocytic Leukemia, страница 5

The treatment of RAS relies on the use of corticosteroids, generally dexamethasone 10 mg intravenously every 12 hours for at least 3 days, begun at the first signs or symptoms of ATRA syndrome.⁶⁸ An alternative approach, used by Australian APL investigators, is to use corticoBte-roids as prophylaxis against RAS, either in allpatients or in patients with rising WBC counts.⁶⁴ It is generally recommended thatATRAbe held or discontinued when RAS is diagnosed or suspected. However, in the analysis of the North American Intergroup trial, eight patients who developed RAS were kept on ATRA (but treated with dexamethasone); all eight patients had resolution of RAS.⁶³ In the European APL 93 trial, among 61 patients who developed RAS, ATRA was stopped in only 30 patients, but few (n = 5) died due to RAS (in this study also, almost all patients with suspected RAS received dexamethasone). The combined results suggest that continuance of ATRA, even in the face of RAS, is probably safe and does not seem to be associated with a higher likelihood of poor outcome, as long as such patients are aggressively treated with corticoste-roids. In any event, if held, ATRA can probably be safely restarted after clinical resolution of RAS, as long as the patient is closely monitored.

CONTROVERSIES IN THE MANAGEMENT OF APL

What Is the Best Induction Therapy?

The central induction question is the potential benefit, if any, of using chemotherapy concurrently with ATRA (ie, at or shortly after diagnosis in all patients, not just those with high WBC counts), versus, for example, starting chemotherapy only after CR has been induced with ATRA (so-called sequential therapy). Although the answer to this question is not known with certainty, preliminary results from the European APL 93 trial⁶⁵ suggest that concurrent ATRA/chemother-apy results in lower relapse rates than sequential ATRA-chemotherapy, although CR rates and 2-year event-free survival are not different (Table 3). In addition, the Italians have reported a 95% CR rate, with 5% early deaths and no cases of resistant leukemia, in the GIMEMA/AIDA trial, in which the induction regimen was ATRA (45 nag/m² until CR) plus four doses ofidarubicin (12 mg/m² on days 2, 4, 6, and 8) in all patients-³ Given these exceptional results; the United States and Canadian Intergroup will use a concurrent ATRA plus anthracycline induction regimen in its next trial, and it appears that the standard of care for induction therapy in APL now consists of ATRA in conjunction with chemotherapy (presumably an anthracycline alone). Left unanswered is whether this regimen is appropriate for all pa-tients (ie, the elderly), or whether the increased cost and inconvenience of an inpatient regimen outweighs the potential benefits of ATRA alone, which can often be given in the outpatient setting.

Recommendations for Consolidation Therapy

In the absence of further data, the guidance in this area is provided by recently published phase III trials. ¹•²•^6S Thus, all patients who achieve CR should receive at least two cycles of consolidation chemotherapy with anthracycline/cytarabine (Ara-0-based regimens, as given in either the North American or European trials.¹.².⁶⁵.⁶⁶ The additional benefit, if any, provided by the Ara-C is difficult to quantify,⁶⁷'⁶⁸ and may be the subject of a future randomized trial by the United States and Canadian Intergroup. Along these lines, it is interesting to note a recent abstract suggests a benefit to high-dose Ara-C as part of induction therapy for APL.⁶⁹ Less controversial is the critical role of anthracyclines in the treatment of APL,⁶⁸ and thus anthracycline dose should not be attenuated unless absolutely necessary.