A Phase III Study of New Synthetic Retinoid Tamibarotene(Am80) Compared with ATRA in Maintenance Therapy for Newly Diagnosed Acute Promyelocytic Leukemia (APL): Japan Adult Leukemia Study Group (JALSG) APL204 Study

ATRA with anthracycline-based chemotherapy markedly improved the prognosis of APL, leading to disease free survival rates 70–80%. But continuous relapse in post-remission period has been a major problem. The role of maintenance therapy for patients in molecular remission after consolidation therapy is uncertain and previous study showed ATRA with or without 6-MP/MTX for 1 to 2 years would be the choice. JALSG APL204 study was intended to decrease the relapse rate in post remission period and applied new synthetic retinoid Tamibarotene (Am80) for maintenance therapy. Am80 is an oral synthetic retinoid with benzoic acid and RARα specific agonist invented in Japan in 1984. High differentiation potential and low affinity to cytoplasmic retinoic acid binding protein may contribute to a superior anti-APL cell effect than ATRA. Early phase II study showed CR rate was 58% for relapsed APL previously treated with ATRA (Blood 90:967–973, 1997). Furthermore Am80 has lower incidence of muco-cutaneous side effects because of no binding affinity to RARγ.

APL204 study was designed as prospective randomized phase III trial comparing Am80 with ATRA in maintenance therapy. Patients (pts) with untreated PML/RARA positive APL between the age of 15 to 69 are eligible. Induction therapy was stratified according to the initial WBC counts: WBC <3,000/μl (Group A: ATRA only), 3,000/μl ≦ WBC <10,000/μl (Group B: ATRA and IDA/Ara-C: 2+5), WBC <10,000/μl (Group C ATRA and IDA/Ara-C: 3+7) and pts who experienced leukocytosis in each group were added chemotherapy (group D). Consolidation chemotherapy consisted of 3 courses containing MIT/Ara-C, DNR/Ara-C and IDA/Ara-C. Patients who achieved molecular remission after consolidation chemotherapy were randomly assigned to 2 groups of maintenance therapy with Am80 at a daily dose of 6 mg/m² divided in 2 doses for 14 days and ATRA at a daily dose of 45 mg/m² divided in 3 doses for 14 days. Each cycle was repeated every 3 months for 2 years and MRD was monitored every 6 months for additional 2 years. Primary endpoint is hematological or molecular relapse-free survival (RFS) during maintenance and follow up period.

Between April 2004 to December 2010, 347 pts were enrolled and 345 pts were evaluable. Median age was 48 (range 16–68) years old, male : female = 183 : 162 and M3 : M3v = 322 : 23. Median WBC count at diagnosis was 700 (70–127,000)/μl and number of pts in each induction group were A=133, B=56, C=70, D=86 pts. In induction therapy, overall CR rate was 94.5% (326/345) and 95.5%(A), 92.9%(B), 88.6%(C), 98.8%(D) in each group. During consolidation therapy 11 pts (3.4%) were dead, including 9 pts (2.8%) for therapy related toxicity and 2 pts (0.6%) for resistant disease. Two hundred and seventy pts (85.7%) were evaluable for maintenance randomization, 134 pts in Am80 and 136 pts in ATRA. With median follow up of 51 (15–97) months, 5-year RFS was 90.9% (Am80) and 83.2% (ATRA) (P=0.1284), OS 92.4% and 98.1% (P=0.3543) in each group. In group C (WBC ≧10,000/μl), 5-year RFS was 87.7% (Am80) and 59.9% (ATRA) (P=0.0297), it was statistically significant, but in group A and B there was no significant differences. Overall relapse rate was 13.7% (37 pts) after randomization. The most frequent adverse effect of Am80 was a transient hyperglycemia. For all patients in APL204 study, 5-year EFS were 76.6%, RFS 82.9%, OS 87.5%.

Maintenance therapy with Am80 has a moderate effect to decrease the relapse rate compared with ATRA but the difference was not statistically significant at 5 years. Both ATRA and Am80 maintenance seem to be effective compared to our previous APL97 study. Notably Am80 is significantly effective in high risk group as WBC ≧10,000/μl (Group C). These results may lead to new strategy for high risk APL. In the future study applying ATO in consolidation therapy and Am80 in maintenance therapy may be a promising strategy to improve the curability and decrease the toxicity of therapy for newly diagnosed APL. This trial was registered at University Hospital Medical Information Network (UMIN)-CTR ID C000000154 in Japan.

No relevant conflicts of interest to declare.