Molecular Classification of Acute Myeloid Leukemia: Are We There Yet?
Authors: Jerald P. Radich
Journal: Journal of Clinical Oncology (2008)

The treatment of acute myeloid leukemia (AML) has made incremental advances during the last few decades, but the outcomes are still fairly grim. Combination chemotherapy can cure approximately 25% of patients. The strongest prognostic factor remains cytogenetics. Patients with “good-risk” cytogenetics have the relatively favorable outcome of disease-free survival (DFS) of approximately 60%; on the opposite side of the spectrum, patients with “unfavorable” cytogenetics have survival of about 10%. The majority of patients fall into the intermediate-risk group, and most of these patients have no abnormal chromosomes at diagnosis. This group comprises approximately 40% of all adult patients, and their DFS is about 25%. Once patients experience relapse, the outcome is especially grim. About half of these patients can be reinduced into a second remission, but conventional chemotherapy will cure few, if any, of these patients. Allogeneic transplantation can cure about 25% of patients placed into a second remission, and fewer if they undergo transplantation in continued relapse. In contrast, transplantation can cure 60% of patients who undergo transplantation in first remission, but the issue remains as to how patients should be selected to undergo transplantation early, and who should get continued chemotherapy with the expectation of a reasonable response. Whereas the cytogenetic risk may help guide that decision for those at the extremes (good or bad risk), what does the clinician do with the considerable number of patients with normal cytogenetics? The promise of using genetics as a deeper approach to understanding the heterogeneity of AML is enormous, but the delivery to the clinic has made slow progress. There are a number of genetic lesions that have been found to be potentially significant in AML. Mutations to the signaling transduction pathway are common in 60% to 70% of AML patients. The first described were point mutations to the guanine triphosphatase protein RAS (principally n-RAS), that are found in 10% to 20% of AML patients. Mutations in the upstream receptor tyrosine kinases can be found in more than 40% of patients, including point mutations in fms and kit, but predominately in FLT3, which increase in frequency from 10% in pediatric patients to 40% in elderly AML patients. Mutations in the FLT3 gene have been shown in several studies to be a strong prognostic factor in both pediatric and adult AML. FLT3 mutations occur in two varieties. The most common is the internal tandem duplication, a head-to-tail duplication of 20 to 300 base pairs in the exons coding for the juxtamembrane region of the molecule. This structural change alters the biology of the FLT3 receptor from normally signaling through ligand-dependent dimerization to that of ligand-independent activation. Tyrosine kinase activation of FLT3 also occurs in 5% to 10% of patients through point mutations in the activating loop of the kinase domain of the molecule. There is an emerging complexity of the relationship of FLT3 mutations and prognosis that is an important object lesson. Though in vitro studies suggest that FLT3-ITD and FLT3-ALM mutations similarly alter signal transduction, FLT3-ITD mutations are clearly associated with a poor prognosis, whereas this association is less clear in patients with FLT3 point mutations. Moreover, not all FLT3-ITD mutations are created equal. Some patients with FLT3-ITD are in a heterozygous state—that is, one mutated, and one wild-type allele. Other patients have clones that are homozygous for the mutated allele. Several studies have demonstrated that the higher the allelic ratio (meaning more mutated v wild-type allele), the worse the prognosis. The prognostic power of FLT3 is increased by combining it with the recently described mutation status of the nucleophosmin (NPM1) gene. Mutations in NPM1 are the most common mutations detected in AML, occurring in 40% of patients. The combination of a wild-type FLT3 with a mutated NPM provides the best prognosis, whereas the worst prognosis is in patients with the FLT3 mutation and wild-type NPM. These associations, along with the emerging field of classification using gene expression, where outcome is associated with the expression of tens to thousands of genes, offer a destination on the long road trip from bench to bedside. New technology and more gene discoveries yield more and more potential candidates to be tested. Predictably, clinicians and scientists are left to say, “Are we there yet?” Two articles in this issue of Journal of Clinical Oncology merge onto this road, further refining the genetic risk of AML based on gene mutations. Paschka et al studied the impact of WT1 mutations in adult AML with normal cytogenetics. WT1 was originally described as a tumor suppressor associated with Wilms’ tumor, but has been shown to be a transcription factor with cell-context– dependent oncogenic properties. WT1 is overexpressed in more than 70% of AML patients, and in some acute lymphoblastic leukemia and myeloid blast crisis chronic myelogenous leukemia. Indeed, some investigators have advocated the use of WT1 expression as a marker of prognosis and residual disease in AML. Mutations in WT1 exon 7 and 9 have been previously reported. In the Paschka et al article, the investigators studied 196 patients, analyzing not only for WT1 mutations, but also FLT3, NPM, and CEBPA mutations, as well as ERG expression, all of which have been JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 28 OCTOBER 1 2008