All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

Abstract

Acute myeloid leukemia (AML) is an aggressive, often fatal hematopoietic malignancy. All-trans retinoic acid (atRA), one of the first molecularly targeted drugs in oncology, has greatly improved the outcome of a subtype of AML, acute promyelocytic leukemia (APL). In contrast, atRA has so far provided little therapeutic benefit in the much larger group of patients with non-APL AML. Attempts to identify genetically or molecularly defined subgroups of patients that may respond to atRA have not yielded consistent results. Since AML is a stem cell-driven disease, understanding the effectiveness of atRA may require an appreciation of its impact on AML stem cells. Recent studies reported that atRA decreased stemness of AML with an FLT3-ITD mutation, yet increased it in AML1-ETO driven or EVI1-overexpressing AML. This review summarizes the role of atRA in normal hematopoiesis and in AML, focusing on its impact on AML stem cells.

Therapeutic Use of Valproic Acid and All-Trans Retinoic Acid in Acute Myeloid Leukemia—Literature Review and Discussion of Possible Use in Relapse after Allogeneic Stem Cell Transplantation

“…Experimental studies suggest that the antileukemic effect of ATRA varies between patients [ 4 , 58 ], and this is further supported by clinical studies. A large phase III clinical trial including 242 elderly patients above 60 years of age described higher response rates and better event-free as well as overall survival in patients receiving ATRA together with conventional intensive induction and first consolidation chemotherapy [ 59 ].…”

“…The effects of ATRA and other vitamin A derivatives in non-APL AML have been reviewed in several recent excellent reviews [ 4 , 6 , 54 , 55 , 56 , 57 ], and for this reason, these effects are briefly described.…”

“…Even low-dose therapy can be effective, and the toxicity seems acceptable. Furthermore, ATRA has been incorporated in several clinical AML trials but not for allotransplant recipients and with divergence; taken together, these results suggest that ATRA therapy has low toxicity and may contribute to the antileukemic effect of combined treatment at least for certain patients or patient subsets [ 4 ]. The combination of valproic acid and ATRA has antileukemic activity and low toxicity [ 35 , 37 ].…”

“…Several experimental and clinical studies have investigated the effects of ATRA combined with valproic acid in the treatment of AML. Important characteristics of the two drugs are summarized in Table 1 [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Additional studies are needed to further characterize the possible mechanisms for interactions between the two drugs at the cellular level, especially whether such interactions differ between patients and depend on karyotype and/or molecular genetic abnormalities.…”

“…Its side effects are well characterized, and severe toxicity is uncommon, dose-dependent, and reversible [ 3 ]. All-trans retinoic acid (ATRA) is widely used in the treatment of acute promyelocytic leukemia (APL), but it may also have antileukemic effects at least for certain patients with non-APL variants of AML ( Table 1 ) [ 4 ]. Valproic acid has therefore been combined with ATRA in several clinical studies of unfit or elderly patients with non-APL AML [ 3 ].…”