Treatment With a New Synthetic Retinoid, Am80, of Acute Promyelocytic Leukemia Relapsed From Complete Remission Induced by All-trans Retinoic Acid

Abstract

Differentiation therapy with all-trans retinoic acid (ATRA) has marked a major advance and become the first choice drug in the treatment of acute promyelocytic leukemia (APL). However, patients who relapse from ATRA-induced complete remission (CR) have difficulty in obtaining a second CR with a second course of ATRA therapy alone. We tested the efficacy of a new synthetic retinoid, Am80, in APL that had relapsed from CR induced by ATRA in a prospective multicenter study. Am80 is approximately 10 times more potent than ATRA as an in vitro differentiation inducer, is more stable to light, heat, and oxidation than ATRA, has a low affinity for cellular retinoic acid binding protein, and does not bind to retinoic acid receptor-γ. Patients received Am80, 6 mg/m2, orally alone daily until CR. Of 24 evaluable patients, 14 (58%) achieved CR. The interval from the last ATRA therapy was not different between CR and failure cases. The clinical response was well correlated with the in vitro response to Am80 in patients examined. Adverse events included 1 retinoic acid syndrome, 1 hyperleukocytosis, 9 xerosis, 8 cheilitis, 16 hypertriglyceridemia, and 15 hypercholesterolemia, but generally milder than those of ATRA, which all patients had received previously. Am80 is effective in APL relapsed from ATRA-induced CR and deserves further trials, especially in combination with chemotherapy.

Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all‐trans retinoic acid and arsenic trioxide

“…Furthermore, the episodes of APL differentiation syndrome were both non-severe and manageable. Tobita et al (1997) have also reported on the use of tamibarotene in the relapsed setting. In their trial, 24 patients with APL who relapsed after ATRA-containing treatment were treated with tamibarotene alone (6 mg/m 2 /d).…”

Salvage of patients with acute promyelocytic leukaemia with residual disease following ABMT performed in second CR using all‐trans retinoic acid

“…Most recently dramatic results have been achieved with the use of arsenic compounds such as AS 2 O 3 ( Shen et al , 1997 ); although experience with these agents is fairly limited to date and as they are not yet widely available their optimal place in the management plan remains to be established. There has also been considerable interest in alternative retinoid differentiating agents to ATRA, including 9‐ cis RA ( Fenaux et al , 1997 ) and synthetic retinoids such as Am80 ( Tobita et al , 1997 ), in the hope that they would circumvent problems with retinoid resistance. However, in the present report we describe the use of ATRA in two children with relapsed APL which was successful despite its prior inclusion as a component of the original induction therapy.…”

All-transretinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells: possible involvement of protein kinase C-δ

“…CD38 probably plays an important role in the development of RAS [6], observed during differentiation-inducing therapy for APL by ATRA, with extensive infiltration of myeloid cells into organs, including lungs, skin, kidneys, liver, and LNs [21][22][23]. RAS was also observed during differentiation therapy by tamibarotene [24]. Based on data of AML M3 NB4 cells in this study, it is predicted that the incidence rate of RAS between ATRA and tamibarotene may not be different.…”