Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21)

Abstract

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).

CBFB Break-Apart FISH Testing: An Analysis of 1629 AML Cases with a Focus on Atypical Findings and Their Implications in Clinical Diagnosis and Management

“…By following this new rule, at least one structural ACA and another numerical ACA are required to define a complex karyotype, which, in turn, did show negative prognostic impact in our previous study [32]. This hypothesis is also supported by Mosna et al [33] and Han et al [28], who suggested that a complex karyotype, if defined by the presence of >= 4 chromosomal abnormalities, is associated with adverse survival in patients with inv(16)/t(16;16) AML. Further investigation is needed to explore the association between ACAs, especially structural ACAs, and prognosis in this cohort.…”

“…FISH testing played an important or even a decisive role in the exclusion of inv(16)/t(16;16) AML in all these scenarios. A confirmation of CBFB rearrangement and consequently the diagnosis of inv(16)/t(16;16) AML are decisive for the clinical management of the patients, e.g., whether to administer cytarabine-based intensive chemotherapy and the likelihood of a favorable response [3,[28][29][30].…”

“…The prognostic impacts of ACAs in inv(16)/t(16;16) AML remain controversial in the literature. For example, Han et al [28] recently reported that trisomy 8 may indicate a good prognosis, whereas all other ACAs (or non-trisomy 8 ACAs) may imply a poorer prognosis in inv(16)/t(16;16) AML patients. However, earlier studies by other groups suggested that trisomy 22 but not trisomy 8 was associated with a better outcome [26,27] or that there was no association between ACAs and prognosis in relapsed inv(16)/t(16;16) AML [24].…”

How to Improve Prognostication in Acute Myeloid Leukemia with CBFB-MYH11 Fusion Transcript: Focus on the Role of Molecular Measurable Residual Disease (MRD) Monitoring

“…The survival analysis of the study revealed different prognostic patterns of cytogenetic factors among the CBF AML subgroups: in inv( 16), chromosomal alterations other than +8 were associated with decreased OS, while trisomy 8 was associated with longer survival. Differently, in t(8;21), hypodiploidy was significant for DFS, whereas hyperdiploidy and del(9q) were associated with improved OS [33]. In the current molecular era, these results confirm the timeless relevance of conventional cytogenetic findings on CBF AML prognosis.…”

“…The number of supplementary chromosome lesions, especially when they are more than 3, in line with other AML subgroups, is associated with a worse outcome [23], according to the prognostic risk scoring by Yoon et al [20]. Recently, Han et al [33] have retrospectively drawn up the largest cytogenetic dataset of CBF AML, therefore characterizing and differentiating the genomic features of the two AML subtypes. Trisomies of chromosomes 8, 21 or 22 recurred significantly more frequently in inv( 16)-bearing patients, in line with previous studies [6,8,19], such as hyperdiploidy.…”