Prognostic Information in AML Gleaned From Timing of Genetic Mutations

Timothy J. Ley, MD

Timothy J. Ley, MD

A new study¹suggests that the presence of persistent genetic mutations, 30 days after induction chemotherapy, predicted relapse and survival in patients with acute myeloid leukemia (AML), as well as intermediate-risk patients. Patients with persistent mutations following induction chemotherapy were about 3 times more likely to relapse and die, compared with those whose mutations cleared after induction chemotherapy.

Genetic profiling at the time of AML presentation did not add prognostic information above and beyond currently used stratification factors.

Although this was a small, retrospective, single-institution study, the findings provide a foundation for future research on the optimal use of genomics, in order to evaluate risk of relapse in the majority of patients with AML. If results are replicated in larger prospective studies, whole-genome sequencing to identify persistent mutations following induction chemotherapy could be used to select patients who should receive allogeneic transplantation and optimize their chances of survival.

"Most patients diagnosed with AML fall into a gray area, when it comes to being able to predict their risk of relapse. About 80% of patients with AML go into remission with chemotherapy, but most will eventually relapse. Unfortunately, we still don't have a definitive test that tells us early on which patients will relapse," stated senior author Timothy J. Ley, MD, the Lewis T. and Rosalind B. Apple Professor of Oncology at Washington University School of Medicine, St. Louis.²

"Such information is important to know because high-risk patients need aggressive, potentially curative therapy with a stem-cell transplant when they are in remission, early in the course of disease. However, we don't want to transplant patients who are unlikely to relapse following conventional chemotherapy, because the transplant procedure is expensive and carries a significant risk of severe side effects and even death," he continued, in a press release from his institution.²

"With deep-exome sequencing, we could identify mutations that could be tracked in the day 30 bone marrow samples that were in remission. If even one mutation was detectable in these samples, it was associated with a 3-fold increase in the risk of relapse. If all mutations were cleared below a threshold of 5% of cells, patients had better outcomes. The patterns of mutation clearance were informative as well: mutations involved in AML initiation often failed to be cleared, while mutations that usually contribute to subclone generation and outgrowth were usually absent on day 30. So, persistence of the founding clone after induction therapy seems to predict a high risk of relapse. This is the information that is missing when you try to assess risk only at presentation. You just cannot make this prediction based on the initial mutations alone," said Ley in an interview withTargeted Oncology.

Study Details

The researchers analyzed bone marrow samples obtained at diagnosis from 71 patients with AML, in order to determine if specific leukemia-related mutations found in each patient were associated with relapse following induction chemotherapy. However, comprehensive genomic sequencing of these 71 patients did not add prognostic value above and beyond standard approaches such as cytogenetics, age, or identification of coding mutations in genes that are recurrently mutated in AML.

The next step in the study was to conduct genome sequencing on bone marrow samples obtained from 50 patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when they were in apparent remission. Of these samples, 24 patients (48%) were found to have persistent mutations in bone marrow cells, despite the fact that they were considered to be in remission by standard criteria.

The presence of persistent mutations was significantly associated with relapse, as measured by event-free survival (EFS) and overall survival (OS).

EFS was a median of 6 months in those with persistent mutations versus 17.9 months in those with cleared mutations (P<.001). Thus, patients with persistent mutations were more than 3.5 times more likely to relapse.

OS was a median of 10.5 months in patients with persistent mutations versus 42.2 months in those with cleared mutations (P= .003), and those with persistent mutations were almost 3 times more likely to die.

Looking at 32 intermediate-risk cases (a gray area for determining prognosis), the presence of persistent mutations after induction chemotherapy was also significantly associated with EFS and OS.

EFS was a median of 8.8 months among 14 intermediate-risk patients with at least one persistent mutation versus 25.6 months for those with cleared mutations (P= .003); patients with persistent mutations were more than 3 times likely to relapse compared with those who have cleared mutations. OS was a median of 19.3 months versus 46.9 months (P= .02). Patients with mutations were almost 3 times more likely to die.

Future Study

Ley said that future plans are to conduct a prospective comparison of mutation clearance, using the deep-exome sequencing method versus a flow cytometric method, for assessment of residual disease in first remission, focusing initially on patients with intermediate-risk AML, who usually have a normal karotype. The investigators want to compare both assays and determine which is best for risk assessment, and ultimately, for selection for allogeneic stem cell transplant.

References:

1. Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia.JAMA.314(8):811-22. doi: 10.1001/jama.2015.9643.
2. Washington University in St. Louis. Relapse, poor survival in acute leukemia linked to genetic mutations that persist in remission.https://news.wustl.edu/news/Pages/Relapse-poor-survival-in-acute-leukemia-linked-to-genetic-mutations-that-persist-in-remission.aspx. Accessed September 2, 2015. ​​​