For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.
Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.
“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”
The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 109/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.
A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.
For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m2 daily in an oral divided dose. Treatments were used until complete remissions were achieved.
Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.
In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.
Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.
Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.
All of the 103 surviving patients achieved complete remissions after consolidation.
The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.