Improving risk assessment of AML with a precision genomic strategy to assess mutation clearance

Timothy Ley

MD

Washington University School of Medicine in St. Louis

Project Term: April 1, 2021 - March 31, 2023

Project Summary

Acute Myeloid Leukemia (AML) is the most common form of acute leukemia in adults. More than 21,450 people will develop AML in the US in 2019, with ~11,000 deaths projected. Although most people who get the disease achieve an initial remission, the majority relapse and eventually die from their disease, usually within two years of presentation. For two decades, the chromosomal profile of AML cells examined at presentation has been used to help predict the risk of relapse. If that risk is high, patients benefit from a stem cell transplant performed during the first remission. But this method is imprecise, especially for the large group of patients who have normal chromosomes, who are said to have “intermediate-risk” disease. Within the past 5 years, nearly all of the mutations that are important for the development of AML have been discovered, and used in an attempt to refine risk assessment. Unfortunately, this approach has had limited success, because of the complexity of the mutations (>250 genes are recurrently mutated, and 2-5 specific mutations cooperate to cause the disease), and the fact that virtually all AML cases consist of several subsets of leukemic cells with different mutational compositions and sensitivities to chemotherapy. Recently, however, we have learned that assessing the clearance of mutations after recovery from initial chemotherapy (using state-of-the-art, next-generation sequencing technologies) may provide a new and more accurate way to assess risk of relapse. If induction chemotherapy eliminates all leukemia mutations from the bone marrow, patients are less likely to relapse, even if they only receive chemotherapy for consolidation. However, if the initial therapy fails to clear all mutations from the bone marrow, patients are more than 3 times more likely to relapse, and die earlier from the disease. We now propose to measure leukemia mutation clearance as a way to decide whether to transplant intermediate-risk patients in first remission. Our hypothesis suggests that the patients who clear all their mutations after initial therapy will do well with chemotherapy alone for consolidation, sparing them the risk of a stem cell transplant from another person, which carries a 10-20% risk of dying from complications of the transplant itself (specifically, graft vs. host disease). Patients who fail to clear all mutations after initial therapy will be offered an immediate stem cell transplant (usually from a matched sibling or unrelated donor), since their risk of relapse is very high. We will compare the time to first relapse in the different treatment arms of the study, and determine whether an improved method for assessing the risk of relapse (i.e. mutation clearance) will result in better decision-making for stem cell transplants, and improved overall survival.