New strategies for the treatment of acute myelogenous leukemia: Differentiation induction - Present use and future possibilities

A differentiation block and an accumulation of immature myeloid cells chara cterize acute myelogenous leukemia (AML), However, native AML cells usually show some morphological signs of differentiation that allow a classificati on into different subsets, and further differentiation may be induced by ex posure to various soluble mediators, for example, all-trans retinoic acid ( ATRA) and several cytokines, Combination therapy with ATRA and chemotherapy should now be regarded as the standard treatment of the acute promyelocyti c leukemia (APL) variant of AML, Although several agents can also induce le ukemic cell differentiation for other AML subgroups, in vitro studies as we ll as clinical data have demonstrated that these agents often have heteroge neous effects on the leukemic progenitors. This makes the clinical impact o f differentiation induction therapy for individual patients difficult to pr edict. However, differentiation induction should be regarded as a promising therapeutic approach, especially as a part of immunotherapy or in combinat ion with intensive chemotherapy to increase the susceptibility of AML blast s to drug-induced apoptosis, Although the morphology-based French-American- British classification was used to identify APL as an AML subset that requi red a special treatment, it seems unlikely that this classification alone c an be used to identify new subsets of AML patients with special therapeutic requirements. Future studies on differentiation induction in AML should th erefore focus on A) the identification of therapeutic agents with more pred ictable effects; B) the use of clinical and laboratory parameters to define new subsets of AML patients in which differentiation induction has a predi ctable and beneficial effect, and C) the characterization of how AML blast sensitivity to drug-induced apoptosis is altered by differentiation inducti on.