Deep sequencing of NPM1 MRD can predict relapse after allogeneic HCT in acute myeloid leukemia

In Leukemia & Lymphoma, a group of Swedish researchers published data from their study which is evaluating the prognostic impact of pre- and post-transplant measurable residual disease (MRD) as assessed by targeted sequencing of NPM1 in adult patients with acute myeloid leukemia (AML). The researchers used a new deep sequencing method which allows for a simultaneous analysis of all recurrent NPM1 insertions. The primary endpoints of the study were overall survival (OS) and relapse-free survival (RFS).

Thirty-two AML patients with a mutation in exon 12 of the NPM1 gene who underwent transplantation between 2005 and 2015 at the Sahlgrenska University Hospital, Gothenburg, or Skåne University Hospital, Lund, Sweden, were included in this study. Of these 32 patients, 29 (median age = 49 years, range; 18–66) were in morphological remission before allogeneic hematopoietic stem cell transplant (HCT).  Levels of NPM1 MRD were measured by deep sequencing at 1 month before allogeneic HCT and 3 months after allogeneic HCT.

Key findings:
  • MRD was determined positive at a variant allele frequency (VAF) ≥ 0.02%
  • Three (12%) patients were MRD+ pre-transplant
  • Five (19%) patients were MRD- post-transplant
  • Pre-transplant deep sequencing MRD positivity associated with worse outcome
  • Post-transplant deep sequencing MRD independently predicts outcome
    • 3-year RFS for post-transplant MRD+and MRD- patients were 20% ± 17.9% and 84.8% ± 8.2% respectively, P < 0.001
    • 3-year OS for post-transplant MRD+and MRD patients were 20% ± 17.9% and 88.6% ± 7.8%, P < 0.001

In summary, MRD analysis using targeted deep sequencing 3 months after allogeneic HCT can predict post-transplant relapse risk in adult patients with NPM1 mutated AML. Key limitations of the study include the small sample size, retrospective nature and limited comparisons with other methods.

The researchers noted that the findings of their study suggest that the “new methodology of targeted deep sequencing can be a valuable tool for monitoring patients with AML with mutated NPM1 and confirm the prognostic impact of MRD positivity before and after” allogeneic HCT.

  1. Delsing Malmberg E. et al. Minimal residual disease assessed with deep sequencing of NPM1 mutations predicts relapse after allogeneic stem cell transplant in AML. Leuk Lymphoma. 2018 Aug 2:1-9. DOI: 10.1080/10428194.2018.1485910. [Epub ahead of print].
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