From March 1993 to October 1993, 20 consecutive, newly diagnosed acute promyelocytic leukemia (APL) patients from 13 Italian institutions entered in a pilot study named AIDA, combining all-trans retinoic acid (ATRA) with idarubicin (IDA). ATRA was administered orally beginning on the first day of induction at the dosage of 45 mg/m2/d until complete remission (CR), whereas IDA was administered intravenously at the dosage of 12 mg/m2/d on days 2, 4, 6, and 8 of the induction. Patients who achieved CR were consolidated with 3 courses of chemotherapy without ATRA; thereafter, they were followed up for molecular and hematologic CR. The median age was 35.3 years (range, 6.5 to 67.6 years); 8 patients were males and 12 females; 4 had the hypogranular variant of APL (M3v), and 4 (2 with M3v) presented with leukocyte counts > or = 10,000/microL. Molecular analysis for the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) hybrid gene at diagnosis was performed in 16 patients by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were RT-PCR+ for the hybrid gene. In the remaining 4 patients, the cytogenetic study showed the presence of the t(15;17). After a median time of 36 days (range, 28 to 52 days) 18 (90%) patients achieved CR; the remaining 2 patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive hemoptysis, respectively. ATRA syndrome was observed in only 2 patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered from the syndrome. However, after recovering, 1 patient achieved CR, whereas the other died at day 34 because of massive hemoptysis; other side effects were very limited. At recovery from the third consolidation course, only 3 of 14 (21.4%) tested patients were RT-PCR+ for the PML-RAR alpha hybrid gene. Of these, 2 relapsed shortly afterwards; however, in the last patient, the PML-RAR alpha disappeared at successive testing performed 2 months later. As of September 30, 1995, after a median follow-up period from diagnosis of 27 months (range, 24 to 31 months), the overall survival and event-free survival durations are 85% and 69%, respectively; moreover, 14 of 18 (78%) patients who achieved CR are still alive and in first molecular and hematologic CR. Of the 4 relapsed patients, 3 achieved a second CR with ATRA and, after further treatment, are now in molecular and hematologic CR after 4+, 16+, and 17+ months from the second CR. These results indicate that (1) the AIDA protocol is highly effective in treating APL; (2) after 3 consolidation courses, the majority of patients who achieved CR are RT-PCR- for the hybrid gene PML-RAR alpha; (3) the persistence of an RT-PCR positivity for the PML- RAR alpha hybrid gene after 3 consolidation courses is indicative of early relapse, thus these patients still require additional treatment. These results have prompted the Gruppo Italiano Malattie Ematologiche Maligne dell′Adulto (GIMEMA) to initiate, in cooperation with the Associazione Italiana di Ematologia ed Oncologia Pediatrica and some European Organization for Research and Treatment of Cancer (EORTC) centers, a new multicentric clinical trial named AIDA LAP 0493 for the treatment of adult and pediatric APL patients. All patients are considered eligible if APL diagnosis is confirmed with molecular or cytogenetic studies for PML-RAR alpha hybrid gene or t(15;17) and are enrolled to receive the same induction and consolidation therapy of this pilot study. After consolidation, patients who are RT-PCR- for PML- RAR alpha hybrid gene are randomized to four arms, whereas patients who are RT-PCR+ after consolidation undergo, if eligible, an allogenic transplantation procedure.

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