ATLANTA – Maintenance therapy with the synthetic retinoid tamibarotene is more effective than all-trans retinoic acid (ATRA), for decreasing the relapse rate in patients with acute promyelocytic leukemia (APL) – a subtype of acute myeloid leukemia, according to 7-year findings from the JALSG-APL204 randomized controlled trial.
The relapse-free survival findings were particularly pronounced among high-risk patients with leukocyte counts of at least 10,000 per microliter,, reported at the annual meeting of the American Society of Hematology.
“These results could lead to a new strategy for the treatment of high-risk patients, which is one of the recent priority issues in the treatment of APL,” said Dr. Takeshita of Hamamatsu (Japan) University.
Of 344 eligible patients aged 15-70 years with newly diagnosed APL and documented cytogenetic and/or molecular evidence of chromosomal translocation t(15;17) or PML/RAR-alpha gene expression, 269 entered the maintenance phase of the study after completing three courses of consolidation therapy and were assigned to receive ATRA or tamibarotene. At a mean follow-up of 7 years, the relapse-free survival rate was 84% in the 135 patients in the ATRA arm, compared with 93% among the 134 patients in the tamibarotene arm.
The difference between the groups was statistically significant, but an even greater difference was seen when the analysis was restricted to 52 high-risk patients with an initial leukocyte count of at least 10,000 per microliter (62% vs. 89%).
Both treatments were generally well tolerated, Dr. Takeshita reported.
Study subjects received ATRA at a daily dose of 45 mg/m2 for remission induction. Once complete remission was achieved, they received chemotherapy based on their initial leukocyte and blast count in the peripheral blood. Those who achieved molecular remission after consolidation chemotherapy were included in the current maintenance phase of the study. During this phase, ATRA was given at a daily dose of 45 mg/m2 divided into 3 doses for 14 days, and tamibarotene was given at a daily dose of 6 mg/m2 divided into 2 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years.
Adverse events included secondary hematopoietic disorders in 12 cases, malignancies in 9 cases, and late cardiac complications of grade 3 or higher in 5 cases, but no significant difference in the rates of these events was seen between the two treatment groups, Dr. Takeshita noted.
Tamibarotene was studied in this trial because, compared with ATRA, it has been shown to have about a 10-fold increase in potency for inducing in vitro differentiation of NB-4 cells, enhanced chemical stability, and low affinity for cellular RA-binding protein.
“The clinical efficacy of tamibarotene for the treatment of APL has also been reported,” Dr. Takeshita added.
In the initial phases of the trial, no difference was seen between ATRA and tamibarotene with respect to 4-year relapse-free survival, but there did appear to be improved efficacy with tamibarotene in high-risk patients, which warranted further investigation, he said.
The current findings demonstrate the efficacy of tamibarotene vs. ATRA for decreasing the relapse rate at the 7-year observation point, and confirm the benefit in high-risk patients that was seen in earlier analyses, he concluded.
Dr. Takeshita reported receiving research funding from Chugai Pharmaceutical, Astellas Pharma, Pfizer Japan, and Takeda Pharmaceutical.
SOURCE: Takeshita A et al., ASH 2017, .