Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia

Abstract

All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combination-based therapy has benefitted newly diagnosed acute promyelocytic leukemia (APL) in short-term studies, but the long-term efficacy and safety remained unclear. From April 2001, we have followed 85 patients administrated ATRA/ATO with a median follow-up of 70 months. Eighty patients (94.1%) entered complete remission (CR). Kaplan-Meier estimates of the 5-year event-free survival (EFS) and overall survival (OS) for all patients were 89.2% +/- 3.4% and 91.7% +/- 3.0%, respectively, and the 5-year relapse-free survival (RFS) and OS for patients who achieved CR (n = 80) were 94.8% +/- 2.5% and 97.4% +/- 1.8%, respectively. Upon ATRA/ATO, prognosis was not influenced by initial white blood cell count, distinct PML-RARalpha types, or FLT3 mutations. The toxicity profile was mild and reversible. No secondary carcinoma was observed, and 24 months after the last dose of ATRA/ATO, patients had urine arsenic concentrations well below the safety limit. These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for de novo APL.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Survival analysis. The 5-year OS (A) and EFS (B) for all 85 patients treated with the ATRA/ATO combination. The 5-year OS (C) and RFS (D) for the 80 patients who obtained CR after ATRA/ATO treatment.

Fig. 2.

Dynamics of PML-RARα and FLT3 ITD in patients treated with ATRA/ATO. (A) In patients who maintained continuous clinical remission, the PML-RARα transcript level was significantly decreased during the treatment and throughout the follow-up. (B) In 2 patients who experienced relapse, the PML-RARα transcript became increased when disease relapse was documented either in CNS or bone marrow. (C) Monitoring of PML-RARα and FLT3 ITD in patients treated with ATRA/ATO at different time courses. End of conso indicates end of consolidation chemotherapy; D, diagnosis..

Fig. 3.

Effects of ATRA/ATO combination on expression of AQP9. (A) In NB4 cells, AQP9 expression was significantly up-regulated after treatment with ATRA/ATO. (B) Expression of AQP9 in bone marrow mononuclear cells isolated from patients on ATRA/ATO treatment in 3 patients (P1–P3). (C) Dynamic changes of AQP9 expression in 8 patients (P1–P8) treated with ATRA/ATO-based regimen. D indicates diagnosis; CS, consolidation therapy.

Fig. 4.

Study on pharmacological features: arsenic concentration in plasma (A), urine (B), nails (C), and hair (D) in different patient groups. (A) The plasma arsenic concentrations of the off-ATO group were considerably lower than those of the on-ATO treatment group (P < 0.001), albeit statistically significantly higher than normal (P < 0.001). (B) Urine arsenic concentrations of the off-ATO group were also lower than those of the ATO treatment group (P = 0.0002) but higher than normal (P = 0.0001). (C and D) Arsenic concentrations in nails and hair of the off-ATO group compared with normal (P = 0.011 and 0.014, respectively). On ATO indicates patients with ongoing ATO treatment; Off ATO, patients treated with ATRA/ATO-based regimen who were at least 24 months off the ATO treatment; Normal, control samples from healthy family members of patients or unrelated healthy blood donors.