Impact of Typical and Atypical Complex Karyotype Subgroups on Outcome of AML Patients Undergoing Allogeneic Stem Cell Transplantation
Authors: Ussmann Jule , Weigert Anne , Bischof Lara , Brauer Dominic , Backhaus Donata , Diener Claudia , Merz Maximilian , Vucinic Vladan , Metzeler Klaus H , Platzbecker Uwe , Schwind Sebastian , Jentzsch Madlen 
Published: December 2023

Introduction
Acute myeloid leukemia (AML) with a complex karyotype (CKT) confers an adverse prognosis, even within the subgroup of patients (pts) with adverse risk according to European LeukemiaNet 2022 (ELN22) risk stratification. Mrózek et al. further characterized CKT pts according to distinct mechanisms of leukemogenesis into balanced (presence of ≥1 balanced rearrangement), and unbalanced CKT (CKT ub, exclusively unbalanced cytogenetic abnormalities). Considering the high incidence of deletions (del) of 5q, 7q, and 17p in CKT, CKT ub were further divided in typical CKT ub (with latter abnormalities present), and atypical CKT ub (with exclusively other abnormalities). In the context of consolidating chemotherapy, typical CKT ub was associated with shorter event-free survival (EFS) and overall survival (OS) compared to atypical CKT ub. However, we lack data in the context of allogeneic hematopoietic stem cell transplantation (HSCT) which remains the preferred treatment in eligible pts. Here we aimed to investigate this classification in CKT AML pts consolidated by HSCT.
Methods
We analyzed 263 pts with AML who were classified as ELN22 adverse risk and underwent an allogeneic HSCT. 105 had a CKT, while 158 fulfilled other ELN22 adverse risk criteria. Of the pts harboring a CKT, median age at HSCT was 61 (range 20 - 76) years. Remission status at HSCT was first complete remission with or without count recovery (CR/CRi, 62%) or refractory AML (38%). Conditioning intensity according to EBMT criteria were myeloablative (19%), reduced intensity (31%) or non-myeloablative (50%). Donors were matched related (16%), haploidentical (2%) or matched (65%) or mismatch unrelated (17%).Cytogenetic analyses at diagnosis were performed using standard techniques of banding and in situ hybridization. Pretreatment genomic DNA was screened for genes recurrently mutated in myeloid malignancies using next generation sequencing. Median follow-up alive was 1.3 years.
Results
Pts with a CKT had a significantly shorter EFS ( P&lt;.01) and OS ( P&lt;.01) than other ELN22 adverse risk pts. Of all pts harboring a CKT, 17% had a balanced CKT, and 83% a CKT ub. Among CKT ub, 85% were classified as typical (67% with del(5q), 49% with del(7q), 26% with del(17p), Figure 1). Comparing typical and atypical CKT ub, pts with typical CKT ub more often had a monosomal karyotype ( P&lt;.01), had more cytogenetic abnormalities (in typical CKT ub median 8 [range 3-39] vs atypical CKT ub median 6 [range 3-9], P=.04), more often TP53 mutations ( P=.02), less often RUNX1 mutations ( P=.03) and a lower LDH at diagnosis ( P=.03). They also had a higher expression of the leukemic stem cell markers CD34+/CD38- ( P=.01) and GPR56 ( P&lt;.01). However, after allogeneic HSCT, EFS ( P=.50) and OS ( P=.50) did not differ between pts with typical and atypical CKT ub (Figure 2).
Next, we looked for other adverse prognostic factors within CKT pts receiving HSCT, which in univariate analyses were the presence of a del(5q) (EFS P&lt;.01 and OS P=.03), a del(17p) (EFS P=.10 and OS P=.02), the presence of ≥5 vs &lt;5 cytogenetic aberrations (EFS P=.03 and OS P=.06), a concomitant TP53 mutation (EFS P=.01 and OS P=.01), and a higher age at HSCT (≥60 years, EFS P=.04 and OS P=.08). In contrast, neither the presence of a del(7q) nor a monosomal karyotype impacted EFS or OS within pts with a CKT. In multivariate analyses for CKT pts, the presence of ≥ 5 cytogenetic aberrations (Hazard Ratio. [HR] 1.7, 95% Confidence Interval [CI] 1.0-3.0, P=.05), higher age at HSCT (HR 1.6, 95% Ci 1.1-2.5, P=.02), and no CR/CRi at HSCT (HR 1.7, 95% CI 1.1-2.7, P=.01) were adverse factors for EFS, while the presence of a del(17p) (HR 2.0, 95% CI 1.2-3.4, P=.01), higher age at HSCT (HR 1.8, 95% CI 1.1-3.0, P=.02), and no CR/CRi at HSCT (HR 1.8, 95% CI 1.1-2.9, P=.02) were adverse factors for OS.
Conclusion
The presence of a CKT retains its negative prognostic impact after HSCT and differentiates within the ELN22 adverse risk group. However, in contrast to chemotherapy consolidation alone, the subgroup of pts harboring a typical CKT ub did not perform worse than pts with an atypical CKT ub, indicating a potential immune-mediated beneficial effect of HSCT. Within pts with a CKT receiving HSCT, we identified additional prognostic factors including the presence of ≥5 cytogenetic aberrations. These pts are in urgent need for novel post HSCT approaches.