Monitoring of Wilms’ Tumor 1 Expression As Minimal Residual Disease in Patients with Acute Myeloid Leukemia to Predict Relapse before and after Allogeneic Stem Cell Transplantation

Background:

Relapse remains the main cause of treatment failure in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The Wilms’ tumor 1 gene (WT1) is reportedly over-expressed in 90% of patients with AML and thus could be useful for minimal residual disease (MRD). However, the clinical utility of WT1 monitoring is still controversial, especially after allo-SCT. The aim of this study was to evaluate the usefulness of WT1 expression as a relapse predictor marker before and after allo-SCT in 160 patients with AML treated in our unit between May 2005 and April 2014.

Patients and methods:

The study included 78 males and 82 females with a median age of 50 years (range, 18-68), who received an allo-SCT for AML. Hematologic status before transplant was complete remission (CR, n=127) and progressive disease (PD, n=33). Donors were HLA-identical sibling (n=57) and unrelated (n=103). Source of stem cells was bone marrow (BM; n=79), peripheral blood stem cell (n=39) and cord blood (n=9). Conditioning was myeloablative in 102 (64%) patients. WT1 expression was assessed by using quantitative real-time PCR and ELN criteria were used to define cut-offs for positive MRD in BM and peripheral blood. Data were retrospectively collected at diagnosis, after the first induction chemotherapy, within a month before transplant, at day 100 post-transplant and at any time point after allo-SCT. A total of 1793 PCR were performed (BM: n=736; peripheral blood: n=1057), including 741 after allo-SCT.

Results:

After a median follow-up of 35 months (4-111), the overall survival (OS), event-free survival (EFS), relapse and non-relapse mortality (NRM) were 58,8%, 55%, 30% and 13,1%, respectively. Thirty-six (22,5%) patients developed acute grade II-IV graft-versus-host disease (GVHD) and 55 (34,4%) chronic GVHD. MRD remained positive after induction chemotherapy in 47/103 (45,6%) evaluable patients, of which 24 reached CR1 before allo-SCT and 23 relapsed. Among MRD negative patients after induction, 25 (44,6%) relapsed before transplant. Post-induction and pre-transplant positive MRD were significantly associated with a progressive disease at transplant (p=0,27 and p<0.001). Only 1 patient with negative pre-transplant MRD was not in CR at transplant. Positive MRD post-transplant was significantly associated with incidence of relapse (p<0.001). MRD was positive in 30/125 (24%) evaluable patients at day 100 post-transplant and in 54/140 (38,6%) evaluable patients at any time point after allo-SCT. Only 7 patients with positive MRD post-transplant did not relapse (MRD became negative without treatment during follow-up). Relapse was observed in 12/95 (12,6%) MRD negative patients at day 100 and only in 1/86 (1.2%) patient with negative MRD at any time after allo-SCT. MRD post-transplant was positive the same day as relapse in 26 cases and predicted relapse in 20 cases, with a median of 74 days (23-683) between the first MRD positive sample and the diagnosis of relapse. Higher WT1 expression post-induction chemotherapy, pre-transplant, at day 100 and at any time post-transplant showed inferior OS (p=0.03, 0.001, <0.001 and <0.001, respectively) and EFS (p=0.009, <0.001, <0.001 and <0.001, respectively). In multivariate analysis, positive MRD post-transplant was the strongest factor adversely influencing OS [HR: 6.42; 95%CI 3.28-12.58] (p<0.001) and EFS [HR: 10.86; 95%CI 5.45-21.72] (p<0.001).

Conclusion:

WT1 expression, even after allo-SCT, can serve as a reliable marker for MRD in AML. Monitoring WT1 expression after allo-SCT could allow early detection of relapse and the subsequent selection of patients who may benefit from modulation of immunosuppression or donor lymphocyte infusion (DLI).