Early Detection of WT1 minimal Residual Disease Predicts Outcome in Acute Myeloid Leukemia and Identify Patients with High Risk of Relapse Independently of Allogeneic Stem Cell Transplantation

Background: WT1 overexpression is frequently identified in acute myeloid leukemia (AML) andhas been reported as a potential marker for minimal residual disease (MRD) monitoring. However, the role of WT1 MRD response as prognostic and/or treatment stratifying factor is still under debate.

Aims: In this work, we evaluated the prognostic value of post-induction WT1 MRD level, as well as the interaction between post-induction WT1 MRD response and the effect of allogeneic stem cell transplantation (SCT) in first complete remission (CR), in a cohort of AML patients aged 18 to 59 years old treated in the Acute Leukemia French Association (ALFA)-0702 trial.

Methods: Among the 713 patients enrolled in ALFA-0702 study (X. Thomas et al, JCO 2017), 539 had an overexpression of WT1 at diagnosis (75.6%) defined as a ratio WT1 transcript/100 ABL transcript above 25% in bone marrow (BM) or 5% in peripheral blood (PB) samples (WT1+). After induction, MRD levels were assessed using cDNA-based real-time quantitative PCR. Occurrence of a WT1 MRD ratio >2.5% in BM or >0.5% in PB was defined here as positive MRD (MRD^pos), while ratio under these threshold was defined as negative MRD (MRD^neg). The prognostic value of MRD was assessed by comparing cumulative incidence of relapse (CIR) with death in remission as competing event, relapse-free survival (RFS) and overall survival (OS) among patients who achieved first CR. As patients with favorable-risk AML according to European LeukemiaNet (ELN)-2010 classification were not eligible for SCT in first CR, interaction between MRD response and SCT effect was evaluated in patients with intermediate/unfavorable-risk AML by comparing the influence of SCT, considered as a time-dependent covariate, on the outcomes of MRD^neg and MRD^pos patients.

Results: Among the 539 WT1+ patients at diagnosis, 473 achieved CR (87.7%). Post-induction WT1 MRD evaluation was available in 339/473 patients (71.7%), 279 patients were MRD^neg and 60 were MRD^pos. At this early time point, MRD was predictive of relapse: 4-year CIR was 36.5% in MRD^neg patients versus 69.2% in MRD^pos patients (Cause-Specific Hazard Ratio, 2.88 [1.93-4.29]; p<0.001). When adjusted on age, cytogenetics, NPM1 mutation status and FLT3-ITD status, MRD remained independently associated with relapse incidence (CSHR, 2.15 [1.41-3.29]; p<0.001). This translated into longer survival in MRD^neg patients. At 4 years, RFS was 60.9% versus 24.9% (HR, 2.69 [1.89-3.83]; p<0.001) and OS was 71.6% versus 43.3% (HR, 2.34 [1.56-3.51]; p<0.001) in MRD^neg and MRD^pos patients, respectively. When adjusted on age, cytogenetics, NPM1 mutation status and FLT3-ITD status, MRD^neg remained independently associated with longer RFS (HR, 2.12 [1.47-3.07]; p=0.001) and OS (HR, 1.79 [1.18-2.73]; p<0.001).

We then analyzed the role of SCT in 254 patients with intermediate/unfavorable-risk AML and available post-induction WT1 MRD evaluation (199 MRD^neg, 55 MRD^pos). SCT was performed in 155 patients. Overall, both MRD and SCT were independent prognostic factors. Post-induction MRD response remained of strong prognostic value, since MRD^pos patients had a higher CIR (CSHR, 2.33 [1.54-3.53]; p<0.001) and a shorter RFS (HR, 2.25 [1.55-3.26]; p<0.001). In this population, SCT was beneficial and significantly improved CIR (CSHR, 0.33 [0.22-0.51]; p<0.001) and RFS (HR, 0.53 [0.37-0.76]; p=0.001). Despite a higher effect of SCT in MRD^neg patients (Figure 1), the interaction between MRD status and SCT effect was not statistically significant (p= 0.3).

Conclusions: Our study confirms the prognostic value of post-induction WT1 MRD in younger adults with AML treated in the prospective ALFA-0702 study. The observation that early WT1 MRD response retains its prognostic value among patients independently of allogeneic SCT in first CR might help selecting these patients more accurately in the next future.

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