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

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/µL or thrombocytopenia < 100,000/μL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD-. Patients without high-risk factors, including Flt3 internal tandem duplication wt/- NPM1-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% MRD-; 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% MRD-, 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 MRD- (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.

Figures

Fig 1.

Overall survival (OS) according to response status after course 1. (A) All patients. (B) Patients at good and standard risk (patients known to be at poor risk excluded). (C) Patients at standard risk. (D) OS for patients at standard risk censored at allogeneic stem-cell transplantation. CR, complete remission; CRi, complete remission with absolute neutrophil count

Fig 2.

Forest plots for overall survival by multiparametric flow cytometry-MRD status for patients in complete remission. (A) After course 1. (B) After course 2, stratified by cytogenetic risk group and NCRI AML17 risk score group. CBF, core binding factor; HR, hazard ratio; MRD, measurable residual disease; NS, not significant; O-E, observed minus expected; Var, variance.

Fig 3.

Forest plots for (A) overall survival and (B) relapse by combined response data after courses 1 and 2. Effect of multiparametric flow cytometry-MRD status in CR after course 2 stratified by post-C1 response status. C1, course 1; CR, complete remission; HR, hazard ratio; MRD, measurable residual disease; NS, not significant; O-E, observed minus expected; PR, partial remission; RD, resistant disease; Var, variance.

Fig 4.

Standard-risk NPM1-wild type. (A) Cumulative incidence of relapse by MRD level. (MRD− v MRD+ < 0.1% v MRD+ ≥ 0.1%) after courses 1 and 2. (B) Overall survival (OS) according to MRD status after course 2 (MRD− v MRD+). (Not shown: MRD+ ≥ 0.1%, OS of 24%; MRD+ < 0.1%, OS of 39%). (C) Mantel-Byar analysis for survival according to first CR stem-cell transplant by MRD after course 2. CR, complete remission; CRi, complete remission with absolute neutrophil count < 1,000/µL or thrombocytopenia < 100,000/μL; HR, hazard ratio; MRD, measurable residual disease; NS, not significant; O-E, observed minus expected; Var, variance.

Fig A1.

Flowchart of treatments given to patients in the NCRI AML17 trial. (A) Pre-October 2011 (induction gemtuzumab ozogamicin randomization). (B) Post-October 2011 (daunorubicin dose randomization in induction). Note: patients who did not satisfy the hepatic entry criteria (liver function 2 with course 2 if they did not receive it by gemtuzumab ozogamicin randomization with course 1. From June, 2012 patients with informative real-time quantitative polymerase chain reaction (RT-qPCR) MRD markers could enter the ‘Monitor vs no Monitor’ randomization that investigates the impact of serial RT-qPCR monitoring post completion of treatment on outcome, quality of life and health economics. ADE, cytarabine, daunorubicin, and etoposide; APL, acute promyelocytic leukemia; CBF, core binding factor; CEP-701, lestaurtinib; DA, daunorubicin and cytarabine; GO, gemtuzumab ozogamicin (3 or 6 mg/m2); FLAG-Ida, fludarabine, cytarabine, GCSF, and idarubicin; FLT3, FMS-like tyrosine kinase-3; mTOR, everolimus; R, randomization.

Fig A2.

CONSORT diagram. Outline of patient sample flow for MRD study. (*) Includes patients for whom remission status could not be classified as exact timing of any remission was unavailable. CR, complete remission; C1, course 1, C2, course 2. LAIP, leukemia-associated–immunophenotype; MRD, measurable residual disease.

Fig A3.

OS according to response status after course 1. (A) All patients. OS censored at allogeneic SCT. (B) NPM1–wild-type patients at standard risk. (C) NPM1–wild-type patients at standard risk, censored at allogeneic SCT. CR, complete remission; MRD, measurable residual disease; OS, overall survival; PR, partial remission; RD, resistant disease; SCT, stem-cell transplantation.

Fig A4.

Forest plots for relapse by multiparametric flow cytometry-MRD status for patients in CR (A) after course 1 and (B) after course 2 stratified by cytogenetic risk group and NCRI AML 17 risk score group. CR, complete remission; MRD, measurable residual disease.

Fig A5.

Cumulative incidence of relapse by multiparametric flow cytometry -MRD level. (MRD− v MRD+ < 0.1% v MRD+ ≥ 0.1%) after course 1. (A) CBF AML. (B) Standard-risk NPM1 mutant. AML, acute myeloid leukemia; CBF, core binding factor; MRD, measurable residual disease; MRD < 0.1%, MRD+ < 0.1%; MRD 0.1%+, MRD+ ≥ 0.1%.

Fig A6.

Standard-risk NPM1-wild type. Overall survival (OS) according to multiparametric flow cytometry-MRD status after course 2, censored at any allogeneic stem-cell transplantation. CR, complete remission; MRD, measurable residual disease.

Fig A7.

OS according to response status after course 1, applying European LeukemiaNet (ELN)/Cheson criteria for PR and RD instead of MRC criteria (ELN criteria for PR: all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25% with decrease of pretreatment bone marrow blast percentage by ≥ 50%). (A) All patients. (B) Patients at good and standard risk (patients known to be at poor risk excluded). (C) Patients at standard risk. (D) Patients at standard risk, OS censored at allogeneic SCT. CR, complete remission; MRD, measurable residual disease; OS, overall survival; PR, partial remission; RD, resistant disease; SCT, stem-cell transplantation.