Genetic Biomarkers in Acute Myeloid Leukemia

Will the Promise of Improving Treatment Outcomes Be Realized?

Jay Yang; Charles A Schiffer

Disclosures

Expert Rev Hematol. 2012;5(4):395-407. 

In This Article

Abstract and Introduction

Abstract

Recent progress in the molecular genetics of acute myeloid leukemia (AML) has shown this disease to be more heterogeneous than previously realized. Recurrent cytogenetic and mutational changes in leukemic blasts have been confirmed to have high prognostic significance. High-throughput techniques to analyze the AML genome in greater depth have revealed novel mutations with putative roles in leukemogenesis. The use of prognostic biomarkers has allowed for a more detailed categorization of AML based on risk. Despite this tremendous progress, the understanding of the mechanisms by which these changes influence leukemia growth and response to treatment is still limited, which in turn has hindered the development of rationally targeted therapies for AML. The integration of clinical, cytogenetic and molecular data will be essential to translate the current research momentum into better outcomes for patients with AML.

Introduction

Acute myeloid leukemia (AML) is a malignancy of hematopoietic progenitor cells committed to the myeloid lineage. It is a disease of older individuals with a median age at diagnosis of approximately 70 years. It has been proposed that the pathogenesis of AML involves the cooperation of class I mutations in oncogenes resulting in a proliferative advantage of the malignant clone and class II mutations in transcription factors resulting in impaired differentiation.[1] The reality is that this model probably represents an oversimplified version of a complex, multistep process that results in AML.

The prognosis of patients with AML is dependent on a large number of patient- and disease-related factors. The amalgam of these factors has been used to place patients into risk groups in an attempt to apply risk-adapted therapies. This approach has resulted in a modicum of success. The rate of overall survival (OS) in younger patients appears to have incrementally improved over the past four decades.[2] Since there have been no significant, newly approved drugs for AML in over 25 years, any improvement in outcomes cannot be explained by chemotherapeutic advances alone. Progress may instead be attributable to risk-adapted approaches, improved outcomes following transplantation and to advances in supportive care. Unfortunately, the outcomes for older patients remain poor without a major trend in improvement.

Recently, there has been a wealth of accumulating data describing novel prognostic markers in AML, aided by the rapid development of sophisticated techniques to analyze the AML genome. This has generated excitement in the AML research community as new insights are being generated at a rapid pace. Aside from the advances seen in the treatment of acute promyelocytic leukemia (APL), which occurred in parallel with, but not dependent on, the molecular biology, the large majority of these breakthroughs have not yet resulted in tangible changes in therapy. This article reviews the prognostic factors in AML with an emphasis on recent developments. The authors also offer an opinion on current and future research trends and their potential significance.

processing....