Post-transplant monitoring of acute myeloid leukemia using next generation sequencing

The allelic burden in patients with acute myeloid leukemia (AML) post allogeneic hematopoietic stem cell transplantation (HCT) has not been longitudinally studied yet. A group of researchers from the University of Toronto, Toronto, ON, Canada, investigated the feasibility and the prognostic value of post-transplant monitoring using next-generation sequencing (NGS) in patients with AML undergoing allogeneic HCT. The results were published in Blood this month.

In this study, bone marrow samples from 104 patients (median age = 42 years; range, 15–63) with AML who underwent allogeneic HCT between January 2004 and November 2015 were analyzed using NGS. Samples were analyzed at the time of diagnosis, pre-HCT, and day 21 post-HCT. At Day 21 post-HCT, variant allele frequency (VAF) ≥ 0.2% (minimum VAF was 0.02) grouped 88 patients (84.6%) as low VAF group and 16 (15.4%) as high VAF group.

Key findings:
  • At diagnosis, 256 somatic mutations were detected in 86.5% (90/104) of patients
    • Median number of mutations per patient: 2 (range, 0–9)
  • From diagnosis to pre-HCT (at the time of complete remission [CR]), there was a significant reduction of VAF rate by 93.12%, P < 0.001
  • There was a significant decrease in the number of VAFs after HCT with an average of VAF of 0.83% post-HCT on day 21 compared to 4.71% pre-HCT
  • Mutations present on day 21 post-HCT, originate from mutations initially detected at diagnosis
  • Survival and relapse post-HCT in patients in the low and high VAF group respectively
    • 3-year overall survival: 67.0 ± 5.1% vs 36.5 ± 12.3%, P = 0.006
    • 3-year relapse incidence: 16.0 ± 3.9% vs 56.2 ± 12.4%, P < 0.001
    • VAF 0.2%-post-HCT on day 21 is an independent risk factor for OS (HR = 3.07 [95% CI 1.48–6.38], P = 0.003) and higher relapse incidence (HR = 4.75 [95% CI, 2.00–11.29], P < 0.001)

In summary, this is the first study to investigate the feasibility of post-transplant monitoring in AML using NGS. The study demonstrates that “post-transplant NGS monitoring on serial samples taken after induction chemotherapy and after allogeneic HCT reveals stepwise clearance of allelic burden from initial AML clone”. Additionally, the presence of allelic burden day 21 post-HCT is prognostic for relapse and survival.

The researchers concluded by stating that their “data and analysis demonstrated NGS-based monitoring of AML patients receiving allogeneic HCT provides valuable information and needs to be combined with the baseline mutational profile and clinical evaluation to predict post-transplant outcome and mortality”.

References
  1. Kim T., Moon, J. H., Ahn, J. S. et al. Next-generation sequencing based post-transplant monitoring of acute myeloid leukemia. Blood. 2018 Aug 14. DOI: 10.1182/blood-2018-04-848028. [Epub ahead of print].
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