The Japan Adult Leukemia Study Group (JALSG) conducted a phase III randomized controlled JALSG-APL204 trial, which aimed to compare tamibarotene, a synthetic retinoid, to all-trans-retinoic-acid (ATRA) in maintenance therapy for newly diagnosed acute promyelocytic leukemia (APL). Previously published data from this study has demonstrated that relapse-free survival (RFS) at four years did not significantly differ between patients treated with ATRA or tamibarotene. 1 However, a longer follow-up for patients is required to accurately evaluate the efficacy of tamibarotene in high-risk patients with APL, thus further investigation was required. The long-term results of this randomized study were published by a group of researchers from the JALSG in Leukemia.
Between April 2004 and December 2010, 347 newly diagnosed APL patients were enrolled in this study with cytogenetic and/or molecular evidence of t(15;17)/PML-RARA. Of these, 344 patients (median age = 48 years) were administered induction therapy, treatment was done according to the initial leukocyte count and blast count in the peripheral blood. ATRA (45 mg/m2 daily) was administered to all patients until complete remission (CR) or for 60 Days. Of the 344 eligible patients, 319 (93%) patients achieved CR.
After completing three courses of consolidation therapy, 269 patients who achieved molecular remission were randomly assigned to two groups of maintenance therapy, and administered tamibarotene (6 mg/m2 daily, n = 134 [median age = 46 years]) divided into 2 doses for 14 days or ATRA (45 mg/m2, n = 135 [median age = 48 years]) divided into 3 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years. The primary endpoint of the study was hematological or molecular RFS during the maintenance and follow up period of 7 years.
- Median follow-up time: 7.3 years (range, 1.8–12.3 years)
- 7-year outcomes for patients in the tamibarotene and ATRA group respectively:
- RFS: 93% vs 84%, HR = 0.44 (95% CI, 0.21–0.93) P = 0.027
- RFS in high-risk patients (n = 52) with an initial leukocyte count ≥ 10 x 109/L: 89% vs 62%, HR = 0.27 (95% CI, 0.07–0.99), P = 0.034
- Cumulative incidence of relapse (CIR): 7% vs 16%, P = 0.025
- Overall survival (OS) after randomization: 97% vs 96%, HR = 0.66 (95% CI, 0.19–2.35), P = 0.261
- Nine patients in the tamibarotene (n = 5) and ATRA (n = 4) arms developed secondary hematopoietic disorders:
- Median time to onset: 2.8 years (range, 0–7.2 years)
- Eleven patients in the tamibarotene (n = 3) and ATRA (n = 8) arms developed secondary malignancies:
- Median time to onset: 5.5 years (range, 1.0–7.9 years)
- Grade 3 cardiac complications occurred in three patients
- There was no difference in the incidence of long-term complications between tamibarotene and ATRA groups
In summary, maintenance therapy with tamibarotene significantly decreased relapse in patients with newly diagnosed APL compared to ATRA. Moreover, tamibarotene was more effective than ATRA in high-risk patients with initial leukocyte count ≥ 10 x 109/L.
This long-term analysis of the JALSG-APL204 trial reveals a “beneficial efficacy for maintenance therapy with tamibarotene for newly diagnosed patients with APL who obtained molecular CR by standard treatment consisting of ATRA and chemotherapy especially in high-risk patients”. The authors concluded that tamibarotene may lead to a new approach for the treatment of APL including the high-risk group.