Measurable residual disease at induction redefines partial response in acute myeloid leukemia and stratifies outcomes in standard- risk patients without NPM1 mutations

Research output: Contribution to journalArticle

Authors

  • Robert Hills
  • Paul Virgo
  • S. Couzens
  • Richard Dillon
  • Amanda Gilkes
  • Laura Upton
  • Ove Juul Nielsen
  • James D Cavenagh
  • Gail Jones
  • Asim Khwaja
  • Paul Cahalin
  • Ian Thomas
  • David Grimwade
  • Alan K Burnett
  • Nigel H Russell

Colleges, School and Institutes

External organisations

  • Cardiff University
  • North Bristol NHS Trust
  • University Hospital of Wales, Cardiff, UK.
  • Division of Genetics and Molecular Medicine, Department of Medical and Molecular Genetics, Kings College London, London, UK
  • St Bartholomews Hosp

Abstract

Purpose
We investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria.
Methods
As part of the NCRI AML17 trial, 2,450 younger adult patients with AML or high-risk myelodysplastic syndrome had prospective multiparameter flow cytometric MRD (MFC-MRD) assessment. After course 1 (C1), responses were categorized as resistant disease (RD), partial remission (PR), and complete remission (CR) or complete remission with absolute neutrophil count , 1,000/mL or thrombocytopenia , 100,000/mL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD2. Patients without high-risk factors, including Flt3 internal tandem duplication wt/2NPM1-wt subgroup, received a second daunorubicin/cytosine arabinoside induction; course 2 (C2) was intensified for patients with high-risk factors.
Results
Survival outcomes from PR and MRD+ responses after C1 were similar, particularly for good- to standard-risk subgroups (5-year overall survival [OS], 27% RD v 46% PR v 51% MRD+ v 70% MRD2; P , .001). Adjusted analyses confirmed significant OS differences between C1 RD versus PR/MRD+ but not PR versus MRD+. CRi after C1 reduced OS in MRD+ (19% CRi v 45% CR; P = .001) patients, with a smaller effect after C2. The prognostic effect of C2 MFC-MRD status (relapse: hazard ratio [HR], 1.88 [95% CI, 1.50 to 2.36], P , .001; survival: HR, 1.77 [95% CI, 1.41 to 2.22], P , .001) remained significant when adjusting for C1 response. MRD positivity appeared less discriminatory in poor-risk patients by stratified analyses. For the NPM1-wt standard-risk subgroup, C2 MRD+ was significantly associated with poorer outcomes (OS, 33% v 63% MRD2, P = .003;
relapse incidence, 89% when MRD+ $ 0.1%); transplant benefit was more apparent in patients with MRD+ (HR, 0.72; 95% CI, 0.31 to 1.69) than those with MRD2 (HR, 1.68 [95% CI, 0.75 to 3.85]; P = .16 for interaction).
Conclusion
MFC-MRD can improve outcome stratification by extending the definition of partial response after first induction and may help predict NPM1-wt standard-risk patients with poor outcome who benefit from transplant in the first CR.

Details

Original languageEnglish
JournalJournal of Clinical Oncology
Early online date30 Mar 2018
Publication statusE-pub ahead of print - 30 Mar 2018