An efficient therapeutic approach to patients with acute promyelocytic leukemia using a combination of arsenic trioxide with low‐dose all‐trans retinoic acid

Abstract

The use of arsenic trioxide (As2O3, ATO) combined with all-trans retinoic acid (ATRA) has recently been reported to induce remission in patients with acute promyelocytic leukemia (APL). However, its efficiency remains inconclusive mainly due to the small number of the available cases. In this study, therefore, we present a clinical study using a combination of ATO with low-dose ATRA (LD-ATRA) to treat 108 APL patients (80 newly diagnosed patients, 28 relapsed patients). Therapeutic outcomes using the ATO/LD-ATRA approach were compared with those of APL patients treated either with ATO alone (65 patients) or ATRA alone (51 patients). The results showed that the ATO/LD-ATRA approach provided significantly better therapeutic outcomes as compared to either ATO or ATRA alone, as evidenced by lower mortality, a higher CR rate and a reduced period to CR. In addition, the toxic side-effects have been no worse with the combined ATO/LD-ATRA treatment than with either ATO or ATRO alone and in some cases have been reduced. These data suggest that the ATO/LD-ATRA regimen is superior to either regimen given alone to patients with APL.

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

“…The detailed information with regard to the dose, time course, interval, and overall regimen design of ATRA, ATO, and chemotherapy during remission induction, consolidation and maintenance therapy has been described previously (16). The benefits of combining ATRA with ATO for newly diagnosed APL, which were statistically significant over a median follow-up of 18 months in our trial, were published in 2004 (16) and got support from some recent reports (18,19), and patients who thereafter entered the trial requested this treatment regimen. As a result of a meticulous evaluation of our trial in terms of both clinical outcome and ethics, we terminated the randomized grouping and prescribed the ATRA/ATO-based regimen for induction and postremission therapy for the maximal benefit of patients.…”

“…We showed that the ATRA/ATO combination significantly shortened the time to achieve CR, reduced disease burden, and enhanced DFS compared with approaches based on the use of either ATRA or ATO as single agents (16). These benefits of the ATRA/ATO-based combination were subsequently confirmed by several groups (17)(18)(19). Being aware of these advances, APL patients entering into our clinical trials preferred ATRA/ATObased treatment to gain maximal therapeutic efficacy.…”

Therapy-induced PML/RARA Proteolysis and Acute Promyelocytic Leukemia Cure

“…As a follow-up to mice studies, several clinical trials were done to see if this therapeutic synergy could be translated into treatment strategies for APL patients. These studies have all shown a striking similarity in APL patients with regard to disease eradication by RA-As (7,(81)(82)(83). Patients treated with a combination of RA and arsenic obtained a quicker clinical response, had a more rapid and complete clearance of leukemic cells, and had a significantly longer period of relapse-free survival.…”

Acute Promyelocytic Leukemia: A Model Disease for Targeted Cancer Therapy

“…These trials are conducted mainly on the basis of successful studies in animal models, showing a positive effect of ATRA/ATO combinations in APL mice (Jing et al, 2001;Lallemand-Breitenbach et al, 1999). The main conclusion so far from the ongoing clinical studies is that newly diagnosed patients are likely to benefit from ATRA/ATO combination treatment in addition to low-dose chemotherapy (Estey et al, 2006;Hu et al, 2009;Shen et al, 2004;Wang et al, 2004).…”

“…While ATRA and ATO on their own are known to be effective in curing APL, it is also becoming increasingly clear that treatment regiments based on a combination of the two drugs leads to a quicker clinical remission, a more effective clearance of leukemic cells and a significantly longer period of relapse free survival (Estey et al, 2006;Hu et al, 2009;Shen et al, 2004;Wang et al, 2004). This synergistic effect may result due to the ability of both these drugs to cause PML/RARA degradation, a parameter that appears to be critical for the success of APL therapy.…”