Persistent, Pre-Leukemic Mutations Help Explain High Relapse Risk in Older Patients with Acute Myeloid Leukemia

Pre-leukemic genetic mutations that persist after chemotherapy are linked to shorter overall survival (OS) and progression-free survival (PFS) in patients with acute myeloid leukemia (AML) who have entered remission, according to research presented at the European Hematology Association’s 21st Congress. Researchers found that these mutations were more common in older patients and may contribute to the higher relapse risk among this population.

“High-throughput sequencing techniques have shown that AML patients in complete morphologic remission may harbor persistent pre-leukemic clones, which might be a source of leukemic relapse,” the authors, led by Maja Rothenberg-Thurley, MD, from Ludwig-Maximilians-Universität Hospital in Munich, Germany, explained.

Dr. Rothenberg-Thurley and colleagues studied the persistence of these driver mutations after patients were in remission and their association with clinical outcomes in 107 patients (median age = 53 years; range = 20-80 years) enrolled in the German AML-CG 2008 trial, comparing sample pairs of driver mutations found in bone marrow or peripheral blood samples obtained at diagnosis and during first remission.

All patients received the same induction chemotherapy that included high-dose cytarabine and achieved either complete remission (CR; 80/107; 75%) or CR with incomplete blood count recovery (CRi; 27/107; 25%).

Ninety percent of patients had de novo AML, five percent had secondary AML, and five percent had therapy-related AML.

Using multiplexed amplicon sequencing, the investigators detected 424 mutations in 42 genes, in 104 patients at diagnosis; at remission, 60 mutations in 15 genes persisted in 38 patients (36%). The most common mutations were of:

  • DNMT3A (62%)
  • TET2 (69%)
  • SRSF2 (63%)
  • ASXL1 (42%)

“Analyses of minimal residual disease (MRD) by flow cytometry or quantitative PCR for NPM1 mutations or MLL-PTD showed similar MRD levels in remission specimens with and without persisting mutations,” the authors reported. “These findings suggest that mutations detected during remission are present in a pre-leukemic clone rather than in residual leukemic cells.”

“Detection of persisting leukemia-associated driver mutations during first CR or CRi is common in older AML patients and likely indicates persistence of a pre-leukemic clone,” Dr. Rothenberg-Thurley added.

Patients who harbored one or more of these persistent mutations during remission tended to be older (median age = 63 years) than patients without mutations (median age = 48 years; p<0.001).

On multivariate analyses adjusting for age, risk group, and remission status (CR vs. CRi), presence of these persistent mutations was associated with shorter PFS and OS, compared with complete mutation clearance:

  • Median PFS = 14.3 vs. 58.0 months (p=0.009)
  • Median OS = 39.6 vs. >72 months (p=0.005)

This translated to a hazard ratio for death of 1.9 for patients with persistent mutations (p=0.04).

These data suggest that more frequent persistence of pre-leukemic clones is one cause for the high relapse rates and poorer prognosis seen in older patients with AML, the authors concluded. Identifying the factors that increase the risk of a poor outcome also raises the possibility that targeted therapies could be used to reduce or eliminate these clones.


Reference

Rothenberg-Thurley M, Amler S, Goerlich D, et al. Persistence of driver mutations during complete remission associates with shorter survival and contributes to the inferior outcomes of elderly patients with acute myeloid leukemia. Abstract #S146. Presented at the EHA 21st Congress, June 10, 2016; Copenhagen, Denmark.

SHARE