Progress toward Better Treatment of Therapy-Related AML

SIMPLE SUMMARY: Therapy-related acute myeloid leukemia (t-AML) is one of the most serious long-term complications of cancer chemotherapy. Various cytotoxic agents and exposure to ionizing radiation can lead to the development of t-AML, which is usually associated with adverse genetic changes and a poor prognosis. Over the past decade, insights into leukemogenesis have generated significant advances in the risk stratification of t-AML, and have offered us the opportunity to develop individualized options for treatment that target disease biology. In this article, we review current knowledge on the biology of t-AML, putting emphasis on its molecular origin; we also discuss recent advances in its treatment including CPX-351, the use of less intensive regimens (e.g., venetoclax combined with a hypomethylating agent), and novel, molecularly targeted and antibody-based therapies that promise to increase the cure rate. ABSTRACT: Therapy-related acute myeloid leukemia (t-AML) comprises 10–20% of all newly diagnosed cases of AML and is related to previous use of chemotherapy or ionizing radiotherapy for an unrelated malignant non-myeloid disorder or autoimmune disease. Classic examples include alkylating agents and topoisomerase II inhibitors, whereas newer targeted therapies such as poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors have emerged as causative agents. Typically, t-AML is characterized by adverse karyotypic abnormalities and molecular lesions that confer a poor prognosis. Nevertheless, there are also cases of t-AML without poor-risk features. The management of these patients remains controversial. We describe the causes and pathophysiology of t-AML, putting emphasis on its mutational heterogeneity, and present recent advances in its treatment including CPX-351, hypomethylating agent plus venetoclax combination, and novel, molecularly targeted agents that promise to improve the cure rates. Evidence supporting personalized medicine for patients with t-AML is presented, as well as the authors’ clinical recommendations.