Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives

Abstract

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique morphological appearance, associated coagulopathy and canonical balanced translocation of genetic material between chromosomes 15 and 17. APL was first described as a distinct subtype of AML in 1957 by Dr Leif Hillestad who recognized the pattern of an acute leukemia associated with fibrinolysis, hypofibrinogenemia and catastrophic hemorrhage. In the intervening years, the characteristic morphology of APL has been described fully with both classical hypergranular and variant microgranular forms. Both are characterized by a balanced translocation between the long arms of chromosomes 15 and 17, [t(15;17)(q24;q21)], giving rise to a unique fusion gene PML-RARA and an abnormal chimeric transcription factor (PML-RARA), which disrupts normal myeloid differentiation programs. The success of current treatments for APL is in marked contrast to the vast majority of patients with non-promyelocytic AML. The overall prognosis in non-promyelocytic AML is poor, and although there has been an improvement in overall survival in patients aged <60 years, only 30%-40% of younger patients are still alive 5 years after diagnosis. APL therapy has diverged from standard AML therapy through the empirical discovery of two agents that directly target the molecular basis of the disease. The evolution of treatment over the last 4 decades to include all-trans retinoic acid and arsenic trioxide, with chemotherapy limited to patients with high-risk disease, has led to complete remission in 90%-100% of patients in trials and rates of overall survival between 86% and 97%.

Keywords: ATRA; acute promyelocytic leukemia; arsenic trioxide.

Figure 1

Comparison of OS in the ALLG APML4 and ALLG APML3 trials. Note: Figure was provided courtesy of H Iland (APML4 principal investigator) from the Australasian Leukaemia and Lymphoma Group APML4 Statistical Report (June 2013) by Collins M, Di Iulio J, and Beresford J (unpublished). Abbreviations: OS, overall survival; ALLG, Australasian Leukaemia and Lymphoma Group; HR, hazard ratio; CI, confidence interval; ATRA, all trans-retinoic acid.

Figure 2

Comparison of DFS in the ALLG APML4 and ALLG APML3 trials. Note: Figure was provided courtesy of H Iland (APML4 principal investigator) from the Australasian Leukaemia and Lymphoma Group APML4 Statistical Report (June 2013) by Collins M, Di Iulio J, and Beresford J (unpublished). Abbreviations: DFS, disease-free survival; ALLG, Australasian Leukaemia and Lymphoma Group; HR, hazard ratio; CI, confidence interval; HCR, hematological complete remission.

Figure 3

Estimated Kaplan–Meier curve for freedom from relapse from documented hematological CR in the APML4 trial, stratified by Sanz risk category. Note: Figure was provided courtesy of H Iland (APML4 principal investigator) from the Australasian Leukaemia and Lymphoma Group APML4 Statistical Report (June 2013) by Collins M, Di Iulio J, and Beresford J (unpublished). Abbreviations: CR, complete remission; HCR, hematological complete remission.