A Multi-Center Retrospective Analysis of Outcomes Post Allogeneic Stem Cell Transplantation in AML Patients with TET2 Mutations: A Study on Behalf of the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Authors: Li Lin , Ye Yishan , Galimard Jacques-Emmanuel , Labopin Myriam , Wu Depei , Chen Jia , Kröger Nicolaus , Passweg Jakob , Salmenniemi Urpu , Itäla-remes Maija , Poiré Xavier , Eder Matthias , Maertens Johan , Burns David , Sengeloev Henrik , Olesen Gitte , Blaise Didier , Finke Jürgen , Gadisseur Alain , Bazarbachi Ali , Brissot Eolia , Nagler Arnon , Luo Yi , Shi Jimin , Ciceri Fabio , Mohty Mohamad , Huang He , Gorin Norbert Claude 
Published: December 2023

Background
Mutations in TET2 present in about 15% of adult AML are reported in some limited series as an adverse prognostic factor for overall survival. However the impact of allogeneic hematopoietic cell transplantation (allo-HCT) for the treatment of these patients remains unclear. We addressed this issue in a EBMT global multi-center registry-based study.
Patients and Methods
644 adult AML patients with TET2 mutations receiving first non ex-vivo depleted allo-HCT from 2013-2022 in 127 centers were analyzed. All patients achieved first complete remission (CR1) before allo-HCT.
Results
The median age of the 644 AML patients was 59.4 (range, 18.1-86.3) years. 556 patients (86.3%) had de novo, and 88 (13.7%) had secondary AML, respectively. 367 (57.2%) patients were male. The median interval from diagnosis to allo-HCT was 4.9 (IQR, 3.8-6.2) months. Patients were categorized into favorable -(N=23, 3.9%), intermediate-(N=475, 79.8%) and adverse (N=97, 16.3%) risk categories according to cytogenetic characteristics. Conditioning regimen was myeloablative (MAC) in 46.7% of patients. 149 patients (23.1%) received a matched-sibling donor, 176 (27.3%) a haploidentical donor (Haplo), 268 (41.6%) a 10/10 unrelated donor (UD) and 51 (7.9%) a 9/10 UD allo-HCT, respectively.
For the entire cohort, with a median follow-up of 1.9 years, the 30-day cumulative incidence of engraftment was 97.6%. The 100-day cumulative incidence of grade II-IV aGVHD was 22.9% and the 2-year cumulative incidence of extensive cGVHD was 13.7%. In addition, the 2-year relapse incidence and NRM were 23.2% and 12.8%, respectively. Finally, the 2-year OS, LFS and GRFS were 69.8%, 63.9% and 49.8%, respectively.
In multivariable analyses, a donor type 9/10 UD was associated with a higher RI (HR=2.33, 95% CI 1.21-4.48; p=0.01), a lower LFS (HR=2.20, 95% CI 1.31-3.70; p&lt;0.01) and OS (HR=2.29, 95% CI 1.33-3.96; p&lt;0.01) as compared to MSD as reference. Compared to MSD, 10/10 UD and Haplo had similar outcomes. The adverse-cytogenetic group was associated with higher RI (HR=1.85, 95% CI 1.19-2.86; p&lt;0.01), and higher incidence of grade II-IV acute GVHD (HR=1.74, 95% CI 1.14-2.64; p=0.01) as compared to other groups combined as reference. Compared to de novo AML (reference), secondary AML was associated with lower LFS (HR=1.49, 95% CI 1.03-2.15; p&lt;0.05) and OS (HR=1.68, 95% CI 1.15-2.45; p&lt;0.01). When age increased, patients faced higher RI (HR for 10y increment=1.24, 95% CI 1.01-1.53; p&lt;0.05) and extensive chronic GVHD (HR=1.34, 95% CI 1.02-1.77; p&lt;0.05), which translated into higher NRM (HR=1.66, 95% CI 1.23-2.24; p&lt;0.01), lower LFS (HR=1.36, 95% CI 1.14-1.62; p&lt;0.01) and OS (HR=1.60, 95% CI 1.31-1.96; p&lt;0.01). Later year of transplantation was associated with lower incidence of II-IV acute GVHD (HR for 2y increment=0.76, 95% CI 0.63-0.92; p&lt;0.01), chronic GVHD (HR=0.67, 95% CI 0.54-0.83; p&lt;0.01) and extensive chronic GVHD (HR=0.72, 95% CI 0.52-0.99; p&lt;0.05). Female to male, patient CMV status and interval between diagnosis and HCT did not affect significantly the transplant outcomes in multivariable analysis.
Conclusion
No significant difference was observed in outcomes of AML patients with TET2 mutations following MSD, HAPLO and 10/10 UD allo-HCTs, while 9/10 UD was associated with higher relapse incidence and lower survival outcomes. Higher patient age, secondary AML and adverse cytogenetics predicted worse transplant outcomes. GVHD prevention improved with time for these patients.