Measurable Residual Disease at Induction Redefines Partial Response in Acute Myeloid Leukemia and Stratifies Outcomes in Patients at Standard Risk Without NPM1 Mutations

Abstract

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. MethodsAs 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. ResultsSurvival 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). ConclusionMFC-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. J Clin Oncol 36:1486-1497. © 2018 by American Society of Clinical Oncology INTRODUCTIONIn acute myeloid leukemia (AML), failure to achieve morphologic complete remission (CR) after a first cycle of induction in previously untreated patients is an established independent prognostic factor from earlier studies. 1-3 Thus, morphologic response at this time point is often incorporated with genetic and pretreatment clinical parameters to guide further therapy, 4 including second induction courses, choice of consolidation, and whether intensification from allogeneic stemcell transplantation (SCT) may be appropriate in otherwise intermediate-risk patients. Despite morphologic response criteria being standard, a differe...

Hematopoietic cell transplantation as treatment of patients with acute myeloid leukemia with measurable residual disease after consolidation therapy

“…While the relapse for such patients is not 100%, it does appear to approach 60%, although as will be explained, it may be possible to reduce the impact of pre-transplant MRD. Similar findings about the impact of MFC detection of MRD has been published by others, including a recent report from Freeman et al concerning the British AML-17 trial [13]. In their study, they found that presence of MFC-detected MRD was highly predictive of overall survival, and that allogeneic transplant benefit was more apparent in MRD+ than in MRD− patients.…”

Induction response criteria in acute myeloid leukaemia: implications of a flow cytometric measurable residual disease negative test in refractory adults

“…Outcome data from multiple previous studies applying MFC to measure residual disease in morphological CR (Schuurhuis et al , ) have contributed to the European LeukaemiaNet (ELN) recommendation that morphological CR without measurable residual disease (CR mrd ‐) be included as a defined response endpoint for AML (Dohner et al , ). CR mrd ‐ by MFC is associated with a significantly better overall survival in younger adults than morphological CR/CR with incomplete blood count recovery (CRi) even after first induction (63% vs. 52% at 5 years) (Freeman et al , ) as previously shown for older patients treated intensively (Freeman et al , ).…”

“…This prompted us to examine the data for discrepant response assessment by standard criteria and flow cytometric MRD results post‐first induction in the three adult AML trials for which outcomes by MFC MRD status in CR have previously reported by the Dutch‐Belgian Haemato‐Oncology Cooperative Group (HOVON) (Terwijn et al , ) and UK National Cancer Research Institute (NCRI) (Freeman et al , , ) trial groups (Table ). MFC MRD samples were more likely to be haemodilute than morphological samples as not prioritised for ‘first pull’ BM.…”

Measurable residual disease testing for personalized treatment of acute myeloid leukemia

“…In case of MRD positivity in BM with negativity in PB at the end of cytoreductive treatment, MRD should be monitored every month for at least 3 months . There is some evidence to suggest that MRD‐positive patients actually may benefit from allo‐HSCT . Conversely, for patients in the intermediate genetic risk group (e.g., concurrent FLT3 ‐ITD), MRD negativity may reduce the likelihood to proceed to transplantation, particularly when other circumstances would argue against allo‐HSCT (e.g., comorbidities).…”

“…After cytoreductive therapy Detectable mutant NPM1 transcripts in BM or PB after two courses of therapy carry a considerable risk of relapse with inferior survival (26,(47)(48)(49)(50)(51)(52). In one study, as many as 82% of MRD-positive patients in PB relapsed compared to 30% of MRDnegative patients (47).…”