Importance of genetic heterogeneity in curing adult acute leukemia (AL)

Abstract

s1 Forty-five years ago adult AL was incurable. Since then we have discovered the striking heterogeneity of AL and its importance in selecting therapy, resulting in cure of increasing numbers of patients. Publication of the French-American-British classification 34 years ago resulted in acceptance that morphology and cytochemistry separated AL into two different diseases, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), that required separate treatment. During the next 15–20 years the importance of cytogenetics in dissecting ALL and AML into entities requiring different therapies became widely accepted, resulting in 2001 in their first incorporation into the World Health Organization (WHO) classification of AL. Over the last 10 years, discovery of molecular abnormalities within cytogenetic groups has further increased our ability to selectively treat and increasingly cure AL. The most striking example of increased curability of AL is acute promyelocytic leukemia, in which targeted therapy combined with chemotherapy has increased survival from a 2-week median to an 80% cure rate. Recognition of increased sensitivity of a genetic subtype of AML to high-dose cytarabine (HiDAC) has increased the cure rate of core-binding factor (CBF) AML from <10%–25% to 55%–60%. Recent discovery of the adverse impact of KIT mutations in CBF AML may allow the addition of tyrosine kinase inhibitors to HiDAC to substantially further increase cure. Among adult de novo AML 40%–45% are cytogenetically normal (CN); the striking molecular heterogeneity of CN-AML is now being recognized and promises to allow individualized approaches that improve substantially upon the current cure rate of 40%. In adult ALL the major adverse subgroup has a Philadelphia chromosome (PH+). New molecularly targeted approaches are allowing remissions in over 90% of PH+ elderly patients and appear likely to substantially cure an increasing fraction of younger PH+ adults. New approaches to studying the leukemia genome and epigenome should improve our understanding of AL heterogeneity, identify new therapeutic targets, and allow the cure of most patients.