Persistent Mutations Linked to AML Relapse, Survival

Chemotherapy-treated acute myeloid leukaemia patients who retain mutations in leukaemia-associated genes during remission have poorer survival and increased relapse risk than those with complete clearance

medwireNews: Preliminary findings suggest that serial monitoring of mutations could prove more useful for predicting prognosis in acute myeloid leukaemia (AML) patients than genomic profiling conducted at a single time point.

Researcher Timothy Ley, from Washington University School of Medicine in St Louis, Missouri, USA, and co-workers carried out a comprehensive genomic analysis, including whole-genome and exome sequencing, of bone marrow samples obtained at diagnosis from 71 patients with AML subsequently treated with a standard induction chemotherapy regimen of cytarabine and an anthracycline.

But the presence of mutations, in either Gene coding or noncoding regions, was not associated with clinical outcomes, leading the authors to say that such an analysis contributes “little additional prognostic value beyond standard approaches”.

However, using samples obtained at two different timepoints from 50 AML patients in complete remission, including 25 from the cohort of 71 patients, they found an association between persistent leukaemia-associated mutations and survival outcomes.

Samples obtained at diagnosis and approximately 30 days after chemotherapy initiation were analysed either by enhanced exome sequencing or by targeted short amplicon sequencing depending on if samples were cryopreserved or preserved in paraffin, respectively.

Twenty-four patients had at least one leukaemia-associated somatic mutation, such as those in DNMT3A or TET2, that was present both in the diagnostic and remission samples – the mean number of persistent mutations was 4.5. The remaining 26 participants showed a complete clearance of diagnostic mutations, defined as a variant Allele frequency of 2.5% or less, which equates to 5% of cells in a sample carrying a particular mutation.

Event-free and overall survival were significantly shorter in participants with persistent mutations than in those who achieved complete clearance, at a median of 6.0 versus 17.9 months and 10.5 versus 42.2 months, respectively.

These findings remained significant when just patients with intermediate-risk disease, based on cytogenetic assessment, were considered. Median event-free survival was 8.8 months for the 14 patients with persistent mutations and 25.6 months for the 18 participants with complete clearance. The corresponding median overall survival times were 19.3 and 46.8 months, respectively.

The team concludes in JAMA: “Although this study was not designed to determine the optimal clearance threshold for the association with outcomes, it represents a foundation for prospective trials focused on the role of digital sequencing to improve risk stratification for AML patients, and perhaps other cancer types as well.”

In an accompanying editorial, Friederike Pastore and Ross Levine, both from the Memorial Sloan Kettering Cancer Center in New York, USA, point out that these data indicate that post-remission therapy aimed at eradicating disease-initiating mutations could become important.

They add: “Although subsequent studies will be needed to validate these findings and to credential clinical-grade assays for dynamic molecular studies, these data illustrate that the depth of remission after initial therapy represents an important parameter that is not sufficiently interrogated in the clinical context.”

Reference

Klco JM, Miller CA, Griffith M, et al. Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia. JAMA 2015;314: 811–822. doi:10.1001/jama.2015.9643

Pastore F, Levine RL. Next-Generation Sequencing and Detection of Minimal Residual Disease in Acute Myeloid Leukemia. Ready for Clinical Practice? JAMA 2015;314: 778–780. doi:10.1001/jama.2015.9452

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