Outcome of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia with Wilms Tumor 1 (WT1) Mutation: A Study from the ALWP/EBMT

Background: The Wilms tumor 1 (WT1) gene is a transcription factor, located on chromosome 11p13, which encodes for a zinc finger protein that has been implicated in regulating cell survival, proliferation, and differentiation and may function both as a tumor suppressor and as an oncogene. Approximately 15% of acute myeloid leukemia (AML) patients (pts) carry WT1 mutations (mWT1), which have been shown to be an independent prognostic factor. Few studies, mostly limited by small sample size, assessed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in pts with mWT1 AML reporting higher relapse incidence (RI) (ref Baranwal A, et al. 2024).

Methods: In a registry-based real-life scenario, this study aimed to assess whether HSCT in pts with mWT1 AML is associated with increased RI and poorer outcomes compared to AML pts with wild-type gene configuration (wtWT1). WT1 mutations were identified by next-generation sequencing (NGS). Patients were transplanted between 2016 and 2022 and all were in first complete remission (CR1) at the time of HSCT. Donors were, unrelated-42.9%, siblings-30.9%, haploidentical-22% or other-4.2%. Univariate analyses were performed using the log-rank test for leukemia-free survival (LFS), overall survival (OS), and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS), while RI and non-relapse mortality (NRM) were calculated using the cumulative incidence (CI) method and compared with Gray’s test.

Results: 751 AML pts with available information on WT1 were included, 64 (9%) with mWT1 and 687 with wWT1. Median follow-up was 2.2 years (95% CI [1.8 – 3]) and 2.4 years [2.2 – 2.6], respectively. The median year of transplant was 2020 (range, 2016-2022) in pts with mWT1 and 2019 (range, 2016-2022) in those with wWT1 (p=0.14). Pts with mWT1 were younger, with a median age of 44.7 (range, 29.3-64.9) vs. 56 (range, 18.2-75.1) years, (p>0.001), and with a higher proportion of females (61.1% vs. 49.5%, p=0.03). Among mWT1 pts a higher frequency of mutations in CEBPA (18.6% vs. 5.3%) (p=0.003) and FLT3-ITD (47.1% vs. 21.3% (p<0.001) genes were observed, together with a lower proportion in the ELN 2022-defined adverse category (15.5 vs. 26.4, p=0.045). Time from diagnosis to HSCT did not differ between the groups, being 4.7 (range, 1.7-23.4) and 4.8 (range, 0.9-23.5) months, respectively (p=0.78). Regarding transplant characteristics, a higher percentage of mWT1 compared to wWT1 pts received myeloablative conditioning: 56.6% vs. 41%, respectively (p=0.003), with busulfan(Bu)/fludarabine (Flu) being the most frequent regimen for the mWT1 group (28.1%) and thiotepa/Bu/Flu being the most frequent regimen for the wWT1 group (32.3%). In addition, in vivo T-cell depletion was used in a higher proportion of mWT1 patients (70.3% vs. 51%, p=0.003). Other transplant characteristics were comparable between both genetic cohorts, including Karnofsky performance status (KPS> 90: 78% vs. 80.3%, p=0.69), frequency of both pt and donor cytomegalovirus seropositivity, female donor to male pt combination (10.9% vs. 14.8%, p=0.4), stem-cell source (peripheral blood in 96.9% vs. 90.8% of the pts, p=0.76) and GVHD prophylaxis, being cyclosporine A /mycophenolate mofetil (MMF) basedin 29.7% vs.25.4%,MMF/sirolimus/tacrolimusin 23.4% vs. 27.8% of transplants, and post-transplant cyclophosphamide in 31.7% vs. 37.8%. The cumulative incidence of absolute neutrophil count >0.5 x 10⁹/L at day 30 was 98.4% vs. 96.5% (p=0.0001). Outcome after HSCT was comparable between both groups (mWT1 vs. wWT1), with 2-year RI (24.6% vs. 22.9%, p= 0.42), NRM (14.2% vs. 14.9%, p=0.54), LFS (61.2% vs. 62.2%, p=0.84), OS (68.2% vs. 69.8%, p=0.78), and GFRS (52.5 vs. 51.8%, p=0.9). GVHD did not differ between the cohorts, with a similar incidence of acute GVHD at day 100 (grades II-IV: 16.1% vs. 21.1, p=0.53; grades III-IV: 4.8 vs. 6.9%, p=0.51) and chronic GVHD (all grades: 26.5% vs. 34.3%, p=0.34; extensive: 6.7% vs. 9.4%, p=0.23). The primary disease was the main cause of death in both mWT1 and wWT1 groups, 57.9% vs. 52% of pts, respectively.

Conclusions: In this retrospective analysis of HSCT for AML in CR1 with comprehensive mutational information, mWT1 did not influence transplant outcomes. Notably, we did not observe higher RI in pts with mWT1, which may indicate that transplantation can overcome the presumed higher risk conferred by this mutational event.