General AML

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

 

Three-year cumulative incidence of relapse (CIR) (%)
[P value]

Three-year overall survival (OS) (%)
[P value]

MP1 vs non-MP1

72.9 vs 13.8 [0.0012]

50.0 vs 88.0 [0.0304]

CP1 vs non-CP1

65.6 vs 9.0 [0.0002]

45.8 vs 91.7 [0.0014]

MP3 vs non-MP3

80.0 vs 11.6 [0.0002]

30.0 vs 94.1 [0.0007]

CP3 vs non-CP3

71.4 vs 8.4 [<0.0001]

53.4 vs 92.5 [0.0021]

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.

References

  1. Bejanyan N.et al. Survival of AML patients relapsing after allogeneic stem cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant. 2015 Mar; 21 (3): 454–459. DOI: 1016/j.bbmt.2014.11.007.
  2. Bader P. et al. Prevention of relapse in pediatric patients with acute leukemias and MDS after allogeneic SCT by early immunotherapy initiated on the basis of increasing mixed chimerism: a single center experience of 12 children. Leukemia. 1999 Dec; 13(12): 2079–2086.
  3. Mo X.D. et al. Preventing relapse after haematopoietic stem cell transplantation for acute leukaemia: the role of post-transplantation minimal residual disease (MRD) monitoring and MRD-directed intervention. Br J Haematol. 2017 Oct; 179(2): 184–197. DOI: 1111/bjh.14778 [Epub 2017 May 23]
  4. Nakamura S. et al. Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS. Blood. 2019 April 1. DOI: 1182/blood-2018-10-880690 [Epub ahead of print]
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