The prognostic role of circulating tumor DNA post-transplant in patients with AML

For patients with acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (allo-SCT) can be a curative approach, however, relapse is a common cause of treatment failure.¹ For patients in relapse, the success of the therapeutic intervention depends largely upon tumor burden.² Therefore, the use of a reliable biomarker for the detection of minimal residual disease (MRD) post allo-SCT can aid in earlier therapeutic intervention and improve outcomes.³

The use of droplet digital PCR (ddPCR) to analyze circulating tumor DNA (ctDNA) post allo-SCT to identify patients with AML and myelodysplastic syndrome (MDS) at high-risk of relapse remains unclear. Sousuke Nakamura, from the Institute of Medical Science, University of Tokyo, Tokyo, JP, and colleagues retrospectively analyzed the impact of residual ctDNA status, at 1 and 3 months post allo-SCT, on outcomes in patients (n = 51; median age = 53 years) with AML/MDS with identified driver mutations.⁴

Patient characteristics and methods

• Patients with de novo AML: 15
• Patients with secondary AML: 22
• Patients with MDS: 14
• Samples were collected:
  • At diagnosis: tumor, matched serum, controls
  • At one month (median time = 32 days; range, 20–40) post allo-SCT: tumor and/or matched serum
  • At three months (median time = 95 days; range, 60–120) post allo-SCT: tumor and/or matched serum
• Patients experiencing relapse: 16/51
• Median time to relapse: 7 months (range, 1.9–53.6)
• Patients with adverse cytogenetic risk: 39.2%
• Patients with relapsed/refractory (R/R) at time of allo-SCT: 49% (25/51)

Key findings

• Median follow-up post allo-SCT: 32 months
• The personalized ddPCR assay demonstrated technical accuracy for the detection of mutations based on tumor and matched serum ctDNA samples from patientsIn 96.2% (51/53) patients, putative driver mutations were identified in 37 genes
• Median mutations per patient: 2 (range, 1–5)
• Most frequent mutations identified by gene type:
• Patients with mutations in epigenetic regulators (TET2, ASXL1, DNMT3A): 32.1%
• Patients with mutations in signal transduction proteins (NRAS, FLT3): 31.4%
• Patients with mutations in spliceosome factors (U2AF1, SF3B1, SRSF2): 21.6%
• Patients with mutation-positive status at one month post allo-SCT (MP1), mutation-positive status at three months post allo-SCT (MP3), ctDNA-positive status at one month post allo-SCT (CP1), and ctDNA-positive status at three months post allo-SCT (CP3), were associated with increased risk of relapse and death compared to patients with molecular MRD-negative status

Table 1: Relapse and survival data for each patient category

• Patients with increasing ctDNA levels between one month and three months post allo-SCT were associated with the highest risk of relapse, compared to patients with a decreasing/stable ctDNA level or negative ctDNA level at both time points (P = 0.0027 and P < 0.0001, respectively)

The authors concluded that non-invasive ctDNA testing had comparable utility to previous, more invasive methodologies for the prediction of patients with AML/MDS at high risk of relapse post allo-SCT. Although large scale, prospective clinical trials are needed to validate these findings, the authors stated that the monitoring of ctDNA may allow rapid clinical decision-making, and timely therapeutic intervention for patients in the post allo-SCT setting.