Digital droplet PCR-based absolute quantification of pre-transplant NPM1 mutation burden predicts relapse in acute myeloid leukemia patients

Ann Hematol. 2018 Oct;97(10):1757-1765. doi: 10.1007/s00277-018-3373-y. Epub 2018 May 22.


Allogeneic hematopoietic stem cell transplantation is an established consolidation therapy for patients with acute myeloid leukemia. However, relapse after transplantation remains a major clinical problem resulting in poor prognosis. Thus, detection of measurable ("minimal") residual disease to identify patients at high risk of relapse is essential. A feasible method to determine measurable residual disease may be digital droplet PCR (ddPCR) that allows absolute quantification with high sensitivity and specificity without the necessity of standard curves. Using ddPCR, we analyzed pre-transplant peripheral blood and bone marrow of 51 NPM1-mutated acute myeloid leukemia patients transplanted in complete remission or complete remission with incomplete recovery. Mutated NPM1 measurable residual disease-positive patients had higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.014). Restricting the analyses to patients receiving non-myeloablative conditioning, mutated NPM1 measurable residual disease positivity is associated with higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.006). Positive mutated NPM1 measurable residual disease status determined by ddPCR before allogeneic stem cell transplantation is associated with worse prognosis independent of other known prognostic markers-also for those receiving non-myeloablative conditioning. In the future, mutated NPM1 measurable residual disease status determined by ddPCR might guide treatment and improve patients' outcomes.

Keywords: Acute myeloid leukemia; Allogeneic hematopoietic stem cell transplantation; Digital droplet PCR; Measurable residual disease.

MeSH terms

  • Adult
  • Aged
  • Allografts
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / blood
  • Bone Marrow / chemistry
  • Bone Marrow Transplantation
  • CCAAT-Enhancer-Binding Proteins / analysis
  • Combined Modality Therapy
  • DNA, Neoplasm / genetics
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology*
  • Leukemia, Myeloid, Acute / therapy
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / blood
  • Neoplasm Proteins / genetics*
  • Neoplasm, Residual
  • Nuclear Proteins / analysis
  • Nuclear Proteins / blood
  • Nuclear Proteins / genetics*
  • Nucleophosmin
  • Peripheral Blood Stem Cell Transplantation
  • Polymerase Chain Reaction / methods*
  • Preoperative Care*
  • Prognosis
  • Recurrence
  • Remission Induction
  • Retrospective Studies
  • Sensitivity and Specificity
  • Transplantation Conditioning / methods
  • Treatment Outcome
  • fms-Like Tyrosine Kinase 3 / analysis


  • Biomarkers, Tumor
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • DNA, Neoplasm
  • NPM1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Nucleophosmin
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3