Impact of ATRA Duration during the Induction Treatment of Newly Diagnosed APL

Background: ATRA combined to anthracycline based chemotherapy (CT) is the reference treatment of newly diagnosed APL. ATRA has also demonstrated a role during maintenance treatment in randomized studies (Fenaux, Blood 99; Talmann, NEJM 1997), and may even be useful during consolidation courses (Sanz, Blood, 2008, although this was not a randomized study). During induction treatment, the optimal duration of ATRA treatment, however, is unknown. We tried to assess this point using long-term results of APL 93 and APL 2000 trials, conducted by the European APL group in newly diagnosed APL between 1993 and 2004.

Methods: APL 93 and 2000 trials combined ATRA plus 3 courses of daunorubicin (DNR) based CT and included a total of 902 pts with different randomizations (for date of introduction of CT, use or not of AraC and of maintenance treatment). Only treatment arms that proved “optimal” (ie with early addition of the first course of CT to ATRA, AraC in combination to DNR for the 3 CT courses, and combined maintenance with intermittent ATRA and low dose continuous CT) (Fenaux, Leukemia 2000;Ades JCO 2006) and adult pts who had achieved CR in those arms, ie 414 pts, were considered for this analysis of the influence of duration of ATRA during induction treatment on the cumulative incidence of relapse (CIR) and survival. Per protocol, ATRA (45 mg/m2/d, rounded to a daily dose of 8 pills of 10 mg per day, ie 80 mg/day in most pts) was to be administered “until CR”, and to be transiently discontinued only in case of severe ATRA syndrome. No dose reduction was allowed except in children, who were therefore excluded from this analysis.

Results: In the 414 pts, who Included 263 (64%) pts with WBC < 10G/L and 151(36%) pts with WBC >10G/L, the median cumulative dose of ATRA administered during Induction treatment was 2160 mg (corresponding to 27 days at 80 mg/d) Early ATRA Interruptions, Ie before recovery from aplasia and patient discharge, were made almost exclusively for ATRA syndrome or unexplained fever, and were followed or not by restart of the drug. Final discontinuation of ATRA for induction treatment was made a median of 27 days after onset of ATRA treatment. Although both trials stated that ATRA should be continued “until CR”, ATRA discontinuation was more often made at the end of the period of aplasia and patient discharge, than at the time of documented CR on bone marrow examination, especially as marrow abnormal promyelocytes are known to disappear slowly in APL. No difference in 5 y CIR or survival were found in pts who had received more or less than 2160 mg of ATRA during induction in the whole population and in pts with baseline WBC less or greater than 10 G/L. 89/414 (21%) pts had received less than 1500 mg of ATRA during Induction (corresponding to less than 19 days at 80 mg/day), their 5 y CIR and survival were similar to those of pts who had received more than 1500 mg of ATRA during induction in the whole population, and in pts with baseline WBC > 10 G/L. However, in pts with baseline WBC <10G/L (263 pts), the 5 year CIR, and survival were 31.3% and 12.5% (p = 0.04) and 81.1% and 95.3% (p = 0.022), in patients who had received less and more than 1500 mg of ATRA during induction treatment, respectively. Differences persisted after adjustment on other prognostic factors of relapse Identified in our previous studies, including gender, baseline platelet count, circulating blasts and fibrinogen level and on the clinical trial (APL 93 vs APL 2000).

Conclusion: Although ATRA duration for induction treatment was not randomized in APL 93 and 2000 trials, our results suggest that, in newly diagnosed APL pts with WBC < 10 G/L, short duration of ATRA during induction treatment may be associated with a higher risk of relapse. This, along with Spanish PETHEMA results supporting a possible role for ATRA during consolidation courses, suggests that sufficiently prolonged exposure to ATRA during the first months of treatment (and not only during maintenance) may be important for disease cure in APL.