HCT-Adapted ELN 2022 Risk Classification: Validation of a Very Poor Risk Group (Adverse-Plus) in AML Patients Undergoing Allogeneic Hematopoietic Cell Transplantation. Study on Behalf of the Grupo Español De Trasplante y Terapia Celular (GETH-TC)
Authors: Jimenez-Vicente Carlos , Salas Maria Queralt , Esteve Jordi , Baile Gonzalez Monica , Martin Calvo Carmen , Oiartzabal Ormategui Itziar , Esquirol Albert , Peña Felipe , Fernandez-Luis Sara , Heras Inmaculada , Gonzalez-Rodriguez Ana Pilar , Lopez Garcia Alberto , Torrado Tamara , Sáez Marín Adolfo Jesús , Acosta Fleitas Cynthia , García Mañó Lucia , Villar Sara , Filafferro Silvia , Basalobre Pascual , Pascual Maria Jesús 
Published: December 2024

Background
In 2022, the European LeukemiaNet (ELN) updated its guidelines for risk allocation in acute myeloid leukemia (AML) patients (Döhner H et al., Blood 2022). Subsequently, a few studies validated externally the prognostic value of this new classification in allografted patients (Jentzsch M et al., Blood Cancer J., 2022 and Jiménez-Vicente C et al, B J Haem 2024). The latter identified a new subgroup, Adverse-Plus (AdvP), with worse outcome if MECOM (EVI1) rearrangement, complex karyotype (CK), TP53 mutation and/or del(17p) were present at AML diagnosis (HCT-Adapted ELN classification)
Methods
This multicenter, retrospective study aims to validate the prognosis ability of the new ELN risk classification with the consideration of the new the subgroup category recently proposed by Jiménez-Vicente C, in AML patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) at 16 Spanish GETH-TC institutions. The study included 651 AML patients who underwent their first allo-HCT in complete morphological response (CR) between 2015 and 2023. All patients achieved CR after at least one line of anthracycline-based induction intensive chemotherapy, with genetic information recorded at diagnosis. Data were updated in May 2024.
Patients were initially categorized into favorable (Fav), intermediate (Int), and adverse (Adv) ELN risk groups based on genetic information. Subsequently, those in the Adv group were further divided into the Adv* and AdvP groups based on the previously mentioned criteria (HCT-Adapted ELN 2022 classification).
Results
The median age of the cohort was 55 years (range 17-74); 52.6% were male, and 84.9% underwent allo-HCT in first CR. Thirty-nine percent of the patients received myeloablative regimens (MAC), and 51.9% received PTCY-based prophylaxis. Grafts were sourced from HLA-matched donors (67.6%), HLA-mismatched unrelated donors (7.4%), and haploidentical donors (28.7%).
According to the HCT-Adapted ELN 2022 classification, 126 patients (19.4%) were in the Fav group, 248 (38.1%) in the Int group, 177 (27.2%) in the Adv group, and 100 (15.4%) in the AdvP group. Baseline characteristics between subgroups were investigated. Compared with the Fav group, AdvP patients were older (median age 58 vs. 53 years, p &lt; 0.001), underwent allo-HCT in first CR (92% vs. 58.7% (p &lt; 0.001).
During follow-up 28.4% of the patients relapsed and 34.5% died. The 2-year overall survival (OS) and leukemia-free survival (LFS) were 80.5% and 71.5% for the Fav group, 72.5% and 66.7% for the Int group, 72.3% and 63.5% for Adv* group, and 37.8% and 32.3% for the AdvP group.
A multivariate regression analysis (MVA) including relevant variables for the allo-HCT [age &lt;55 years (vs. younger), AML type (De novo vs. Secondary/Therapy-Related), MRD positive status prior to allo-HCT (vs. negative), reduced intensity conditioning regimen (vs. myeloablative) PTCY-prophylaxis (vs. others), HLA-matched donor (vs. others) and first CR (vs. others)] confirmed the poor prognosis of the AdvP group. Compared with the Adv* group, patients within the AdvP group had lower OS (HR: 3.05, p &lt; 0.001) and LFS (HR: 2.66, p &lt; 0.001). Age &gt;55 years (OS (HR: 1.72, p = 0.002), LFS (HR: 1.41, p = 0.011) and a positive MRD status prior to allo-HCT (OS (HR: 1.49, p = 0.007), LFS (HR: 1.51, p = 0.002) were associated with lower OS and LFS. Interestingly, the outcome of Adv* risk patients was similar to Int (OS (HR: 1.02, p = 0.90), LFS (HR: 1.17, p = 0.37)
Further investigations were conducted among the 100 patients in the AdvP group, based on genetic abnormalities identified at diagnosis. Of these patients, 22% had MECOM(EVI1) rearrangements, and 78% had a CK and/or TP53 mutations. Within this subgroup, 62% of the patients relapsed and 67% died. Furthermore, the estimated 2-year OS and LFS were 51% and 40% for patients with MECOM(EVI1) rearrangements, and 34% (p = 0.04) and 30% (p = 0.07) for those with CK and/or TP53 mutations.
Conclusion
The study validates the ELN 2022 risk classification as a prognostic marker for allo-HCT outcomes in AML patients in CR, confirming also the poorer outcome in the Adv group, attributable to patients subclassified under the new AdvP risk category. This information provides relevant information on relapse risk after allo-HCT, facilitate patient counseling, and warrants the design of specific transplant strategies for this AdvP subgroup to prevent post-transplant relapse.