APL treatment Italian style: is this the cure?

Comment on Testi et al, page 447

In this issue of Blood, Testi and colleagues report the results of an Italian therapeutic trial for pediatric acute promyelocytic leukemia (Gruppo Italiano per le Malattie Ematologiche dell'Adulto–Italian Pediatric Hematology and Oncology Group [GIMEMA-AEIOP] ATRA and idarubicin [AIDA]). These remarkable results suggest that APL is now a totally curable disease for the vast majority of children with APL, but at a cost: late cardiac or marrow failure.

The treatment program for pediatric APL consisted of 3 phases: induction, consolidation (3 separate cycles), and maintenance. The unique features of this treatment include: very high-dose anthracycline induction (48 mg/m² idarubicin, which equals approximately 240 mg/m² daunorubicin) and consolidation (20 mg/m² idarubicin and 50 mg/m² mitoxantrone); use of different types of anthracyclines; use of lower doses of all-trans retinoic acid (ATRA, 25 mg/m² per day) than has been used in the United States (45 mg/m² per day); and bone marrow transplantation for molecularly defined persistent or recurrent acute promyelocytic leukemia (APL). No intrathecal therapy was given.

All evaluable patients (aged < 18 years) had molecular evidence of APL. From January 1993 to June 2000, 124 children from 42 different centers were enrolled. Induction of complete remission (CR) was achieved in 96% of all eligible patients (n = 110) and in 100% of those with a diagnostic white blood cell (WBC) count of 10 × 10⁹/L (10 000/μL) or less (n = 72). The overall survival at 10+ years was 89%, with event-free survival at 76%. It was determined that no child experienced a chemotherapy induction failure. The patients who did not attain CR were all early deaths (days 1, 9, and 16 from intracranial hemorrhage; day 34 from infection), and all had WBC counts at diagnosis above 10 × 10⁹/L (10 000/μL). Almost all relapses were seen in patients with diagnostic WBC counts of more than 10 × 10⁹/L (10 000/μL), and there were no central nervous system (CNS) relapses. Overall survival for patients with a diagnostic WBC count of 10 × 10⁹/L (10 000/μL) or less was 94%.

Given the total number of patients studied and the length of the follow-up, these results are the best reported to date in pediatrics. However, these results come at a price. Two patients developed myelodysplasia (MDS; at 36 and 80 months from initial diagnosis) and subsequently underwent transplantation. One has survived at 16 months from the MDS diagnosis. The other “cost” is cardiac health. Although the authors do not report any clinically significant cardiac effects, it appears that the collection of cardiac testing results in long-term follow-up has not been completed. Certainly congestive heart failure (CHF) and cardiac deaths are reported in APL patients following much lower total anthracycline dosing (patients fully treated by this regimen would get the equivalent of 650 mg/m² daunorubicin).^1,2 

The results of this trial for “good-risk” patients with APL suggest that their treatment could be reduced in the future, thereby possibly reducing the risks for MDS and/or cardiac damage. Agents that are more specific for APL and/or less globally cytotoxic, including arsenic trioxide and gemtuzumab ozogomycin, are already available.^3-5  Early reports of their use in newly diagnosed patients strongly suggest that these agents should be introduced earlier in the treatment of patients with APL. ▪