Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia

A prospective multicenter study was performed to investigate the clinical a nd molecular results of intensified double induction therapy including high -dose cytarabine (ara-C) in combination with ATRA in newly diagnosed acute promyelocytic leukemia (APL), followed by consolidation and 3 years mainten ance therapy. Fifty-one patients, diagnosed and monitored from December 199 4 to June 1999, were evaluated. The median age was 43 (16-60) years. The mo rphologic diagnosis was M3 in 40 (78%) and M3v in 11 (22%) patients. In 15 (30%) patients the initial white blood cell counts were greater than or equ al to 5 x 10(9)/l. The cytogenetic or molecular proof of the translocation t(15;17) was a mandatory prerequisite for eligibility. The diagnosis was co nfirmed by karyotyping in 46 and by RT-PCR of the PML/RAR alpha transcript in 45 cases. The rate of complete hematological remission was 92% and the e arly death rate 8%. Monitoring of minimal residual disease by RT-PCR of PML /RAR alpha (sensitivity 10(-4)) showed negativity in 29 of 32 (91%) evaluab le cases after induction, in 23 of 25 (92%) after consolidation, and in 27 of 30 (90%) during maintenance, after a median time of 2, 4 and of 18 month s after diagnosis, respectively. After a median followup of 27 months, the estimated actuarial 2 years overall and event-free survival were both 88% ( 79, 97), and the 2 years relapse-free survival 96% (90, 100). The high anti leukemic efficacy of this treatment strategy is demonstrated by a rapid and extensive reduction of the malignant clone and by a low relapse rate. The results suggest that the intensity of the induction chemotherapy combined w ith ATRA is one of the factors which may have a critical influence on the o utcome of APL. A randomized trial should assess the value of an induction t herapy including ATRA and high-dose ara-C in comparison to standard-dose ar a-C.